Anticancer potential of quercetin: A comprehensive review

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SEE PROFILE Received: 1 February 2018 Revised: 18 June 2018 Accepted: 21 June 2018 DOI: 10.1002/ptr.6155 REVIEW Anticancer potential of quercetin: A comprehensive review Abdur Rauf1 | Muhammad Imran2 | Imtiaz Ali Khan3 | Mujeeb‐ ur‐Rehman4 Syed Amir Gilani5 | Zaffar Mehmood5 | Mohammad S. Mubarak6 | 1 Department of Chemistry, University of Swabi, Ambar, Pakistan 2 Diet plays a key role to maintaining healthy life. Many natural products present in our University Institute of Diet and Nutritional Sciences, Faculty of Allied Health Sciences, The University of Lahore‐Pakistan diet, such as flavonoids, can prevent the progression of cancer. Quercetin, a distinc- 3 dietitians and medicinal chemists due to its numerous health‐promoting effects. It is Department of Agriculture, University of Swabi, Sayed, Pakistan tive bioactive flavonoid, is a dietary component that has attracted the attention of an outstanding antioxidant that has a well‐documented role in reducing different 4 H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan 5 Faculty of Allied and Health Sciences, University of Lahore, Lahore, Pakistan 6 Department of Chemistry, The University of Jordan, Amman, Jordan Correspondence Dr. Abdur Rauf, Department of Chemistry, University of Swabi, Anbar 23430, Khyber Pakhtunkhwa, Pakistan. Email: [email protected] Prof. Mohammad S. Mubarak, Department of Chemistry, The University of Jordan, Amman 11942, Jordan. Email: [email protected] human cancers. Quercetin exhibits direct proapoptotic effects on tumor cells and thus can inhibit the progress of numerous human cancers. The anticancer effect of quercetin has been documented in numerous in vitro and in vivo studies that involved several cell lines and animal models. On the other hand, the high toxic effect of quercetin against cancer cells is accompanied with little or no side effects or harm to normal cells. Accordingly, this review presents an overview of recent developments on the use of quercetin against different types of cancer along with mechanisms of action. In addition, the present review summarizes the literature pertaining to quercetin as an anticancer agent and provides an assessment of the potential utilization of this natural compound as a complimentary or alternative medicine for preventing and treating cancer. KEY W ORDS cancer prevention, human cancers, mechanisms of action, quercetin 1 | I N T RO D U CT I O N such as capers, lovage, dill, cilantro, onions, apples, and berries as in chokeberries, cranberries, and lingonberries. Perhaps, the most impor- Flavonoids are abundantly present in nature in the form of benzo‐γ‐ tant property of this flavonoid is its antioxidant effect. In addition, pyrone derivatives. Plants, vegetables, and flowers are the major quercetin can be useful in cancer prevention (Iacopetta et al., 2017) sources of these compounds. Structurally, flavonoids have diverse and is known to have antiallergic, anti‐inflammatory, and antiviral frameworks with interesting biological properties and can play an activities (Y. Liu et al., 2017). Most importantly, quercetin impedes important role in the body's defense system. The beneficial effects the propagation of various types of cancers, such as lung, prostate, of flavonoid‐rich foods have been demonstrated by various studies liver, breast, colon, and cervical (Y. Liu et al., 2017); these anticancer (Benavente‐Garcia & Castillo, 2008). There are more than 4,000 types properties are exerted through various mechanisms that involve cellu- of various flavonoids in nature with diverse subcategories, such as fla- lar signaling and the ability to inhibit enzymes responsible for the acti- vones, isoflavones, flavanones, and chalcones. Amongst the various vation of carcinogens. Quercetin displays anticancer effects based on promising health benefits, flavonoids possess important biological its binding to cellular receptors and proteins (Murakami, Ashida, & activities, such as anti‐inflammatory, antioxidant, hepato‐protective, Terao, 2008; Shih, Pickwell, & Quattrochi, 2000). Furthermore, quer- and antimicrobial properties (Kanadaswami et al., 2005). cetin has been recently reported to have synergistic effects when Quercetin (Figure 1), 3,3′,4′,5,7‐ combined with chemotherapeutic agents such as cisplatin, which pentahydroxyflavone (C15H10O7), is a naturally occurring polyphenolic may further improve the outcomes of the traditional chemotherapy flavonoid that is commonly found in different fruits and vegetables (Brito et al., 2015). Phytotherapy Research. 2018;1–22. chemically known as wileyonlinelibrary.com/journal/ptr © 2018 John Wiley & Sons, Ltd. 1 RAUF 2 ET AL. apoptosis and mRNA expression levels. In addition, quercetin was found to sensitize MCF‐7 cells to doxorubicin (Dox) and reduce cellular NAD(P)H quinone oxidoreductase 1 and multidrug resistant protein 1 gene expression levels (Minaei et al., 2016; Suksiriworapong et al., 2016). Similarly, treatment of MCF‐7 and MDA‐MB‐231 breast cancer cell lines with quercetin led to apoptosis along with G1 phase arrest FIGURE 1 Quercetin and considerably suppressed the expression of Twist, CyclinD1, p21, and phospho p38 mitogen‐activated protein kinases (p38MAPKs). It As soon as quercetin is absorbed in the gastrointestinal tract, it has also effectively controlled the expression of Twist, which induces gets metabolized by phase II enzymes present in the epithelial cells apoptosis in MCF‐7 cells due to p16 and p21. These findings suggest of the stomach and intestines. The combined metabolites are then fur- that quercetin induces apoptosis in cancer cells via suppression of ther processed in the liver and kidney (Abarikwu, Pant, & Farombi, Twist through p38MAPK (Liao et al., 2015; Ranganathan, Halagowder, 2012; Nabavi, Nabavi, Mirzaei, & Moghaddam, 2012). Mechanistically, & Sivasithambaram, 2015). the catechol structure (B‐ring) is methylated at the 3′ or 4′ hydroxyl Research published by Dhumale and coworkers demonstrated sites by catechol‐O‐methyl transferase to produce isorhamnetin and that receptor for advanced glycation end‐products (RAGE), which is tamarixetin, respectively. Quercetin metabolites seem to accumulate a multi‐ligand member of the immunoglobulin superfamily, plays an in tissues shortly after quercetin‐rich vegetables are consumed. In important role in maintaining cellular homeostasis. The elevated vitro studies indicated that quercetin metabolites, originating from expression of RAGE and its ligand high‐mobility group box proteins‐ enterocytes and the liver, serve as antioxidants by impeding oxidation 1 (HMGB‐1) was found in different types of cancer. In addition, aggre- of low‐density lipoprotein cholesterol. gation of RAGE with its HMGB1 stimulates a complicated signaling On the other hand, and even with the many technological and network for cell viability and avoids apoptosis. Hence, quercetin aug- pharmaceutical advances over the past two decades, cancer continues ments apoptosis in MCF‐7 cells by hindering the expression of RAGE to be a global concern (Seyed, Jantan, Bukhari, & Vijayaraghavan, and HMGB1; this also results in necrotic insult (Dhumale, Waghela, & 2016). Scientists attribute 90–95% of all cancers to lifestyle including Pathak, 2015). Furthermore, lack of estrogen, progesterone, and epi- obesity, outdoor pollution, alcohol consumption among others, dermal growth factor‐2 receptors is the typical indicators of triple neg- whereas the remaining 5–10% are attributed to defective genes (de ative breast cancer (TNBC). Quercetin can induce the expression of E‐ Martel et al., 2012). Cancer treatment methods include surgery, radio- cadherin and suppression of vimentin levels in TNBC. It has also therapy, and anticancer drugs (chemotherapy) in addition to other spe- shown the potential to regulate these epithelial mesenchymal transi- cialized techniques. For years, humans have used herbs as tion (EMT) markers resulted in a mesenchymal‐to‐epithelial transition. complementary therapy or dietary agents to treat different types of In addition, quercetin stimulates antitumor activity of Dox by attenu- cancer and to influence cellular signaling (Martin, 2006). In this regard, ating the migratory ability of TNBC cells (Srinivasan et al., 2016). natural compounds such as quercetin have been employed as alterna- Recent studies indicated that quercetin can enhance the chemo‐ tive drugs in the treatment of cancer. Based on the above discussion, sensitivity of breast cancer cells to Dox via inhibiting cell proliferation and owing to the wide range of therapeutic options of quercetin and invasion, resulting improvement in cell apoptosis, and modulating against various types of cancer, this review focusses on the current expression of phosphatase and tensin homolog and p‐Akt (S. Z. Li, knowledge on the chemo‐preventive and therapeutic ability of this Qiao, Zhang, & Li, 2015). Moreover, quercetin has exhibited the inhib- natural flavonoid against different types of cancer, along with its itory effect on MCF‐7 and MDA‐MB‐231 human breast cancer cell mechanisms of action. For this purpose, recent relevant references lines through multiple mechanisms such as up‐regulation of miR‐ have been obtained from different databases such as MEDLINE 146a expression, induction of apoptosis, activation of caspase‐3 and (PubMed), Google Scholar, ScienceDirect, Scopus, Cochrane, SID, mitochondrial‐dependent pathways, and down‐regulation of the and SciFinder. We hope this review will be a valuable addition to the expression of epidermal growth factor receptor (EGFR; Tao, He, & field and will be a great help for researchers. Listed in Table 1 are Chen, 2015). It also lowers the tumor number (Metastasis), tumor vol- the anticancer perspectives of quercetin along with the mechanisms ume, down‐regulates 31 genes, and up‐regulates 9 genes in human in each type of cancer with a list of pertinent references, whereas breast cancer (Steiner et al., 2014). shown in Figure 2 is the anticancer role of quercetin. Below are details about documented anticancer activities of quercetin. In breast malignancies, epidermal growth factor plays a critical role by propagating cell proliferation, angiogenesis, and metastasis. Silver nanoparticle‐based quercetin caused a significant reduction in the expression of various proteins including vimentin, Snail, N‐cadherin, 2 | ANTI CANCER PERSPECTI V ES OF QUERCETIN Twist, Slug, matrix metalloproteinase‐2 (MMP‐2), MMP‐9, vascular endothelial growth factor receptor 2 (VEGFR2), p‐EGFR, protein kinase B (Akt), phosphoinositide 3‐kinase (PI3K), and glycogen syn- 2.1 | Breast cancer thase kinase 3 beta (p‐GSK3β) and enhanced E‐cadherin protein expression in 7,12‐dimethylbenz[a]anthracene‐induced mammary car- Recent research revealed that treatment of Michigan Cancer Founda- cinoma in Sprague–Dawley rats. It also reduced cell viability and cap- tion‐7 (MCF‐7) breast cancer cells with nano‐quercetin enhances illary‐like tube formation, suppressed tube and new blood vessel RAUF ET AL. TABLE 1 3 Anticancer perspectives of quercetin, along with mechanisms of action Cancer types Mechanisms References Breast cancer Increases cell apoptosis and inhibits cell cycle progression Increases FasL mRNA expression and p51, p21, and GADD45 signaling activities. Induces protein level, transcriptional activity, and nuclear translocation of Foxo3a Nguyen et al. (2017) Reduces downstream genes including NQO1 and MRP1 Minaei, Sabzichi, Ramezani, Hamishehkar, and Samadi (2016) and Suksiriworapong et al. (2016) Down‐regulates the vimentin levels and modulates the epithelial mesenchymal transition (EMT) markers Srinivasan et al. (2016) Reduces the expression of vimentin, Snail, N‐cadherin, Twist, Slug, metalloproteinase‐2 (MMP‐2), MMP‐9, VEGFR‐2, p‐EGFR, Akt, p‐phosphoinositide 3‐kinase (PI3K), and p‐GSK3β Enhances E‐cadherin protein expression Balakrishnan et al. (2016) and Quagliariello et al. (2016) Causes cell cycle arrest and apoptosis in breast cancer cells via regulation of Akt and Bax signaling mechanistic pathways Sarkar, Ghosh, Chowdhury, Pandey, and Sil (2016) Upregulates the levels of cleaved caspase‐8 and caspase‐3 Suppresses the expression of phospho‐JAK1 and phospho‐STAT3 Decreases STAT3‐dependent luciferase reporter gene activity (BT‐474 cells) Seo et al. (2016) Inhibits the expression of P‐glycoprotein Lv et al. (2016) Colon cancer Pancreatic cancer Liver cancer Lung cancer Kee et al. (2016) Inhibits the cell viability of CT26 and MC38 colon cancer cells Induces apoptosis through the mitogen‐activated protein kinases (MAPKs) pathway Regulates the expression of EMT markers, such as E‐, N‐cadherin, β‐catenin, and snail Causes G2 phase arrest Induces autophagic cell death through ERK activation Y. Zhao, Fan, et al. (2017) and J. Zhao, Liu, et al. (2017) Enhances the expression of E‐cadherin protein Decreases the expression of metastasis‐related proteins of MMP‐2 and MMP‐9 Reduces the production of different inflammation factors including TNF‐α, IL‐6, and Cox‐2 M. Han, Song, and Zhang (2016) Reduces the expression levels of cellular FLICE‐like inhibitory protein Activates c‐Jun N‐terminal kinase (JNK) J. H. Kim, Kim, Choi, and Son (2016) and Nwaeburu et al. (2016) Reduces the tumor growth and drug resistance Cao et al. (2015) Suppresses epidermal growth factor‐induced movement action Inhibits the EGFR‐mediated FAK, AKT, MEK1/2, and ERK1/2 signaling pathway J. Lee, Han, et al. (2015), W. J. Lee, Hsiao, et al. (2015), Y. J. Lee, Lee, and Lee (2015), and S. H. Lee, Lee, Min, et al. (2015) Activates caspase‐3, ‐8, and ‐9 and reduces the mitochondrial membrane potential Inhibits extracellular signal‐regulated kinase (ERK) phosphorylation and promotes JNK phosphorylation F. Y. Chen, Cao, et al. (2015), X. Chen, Dong, et al. (2015), and Q. Chen, Li, et al. (2015) Induces apoptosis Guan, Gao, Xu, et al. (2016) Down‐regulates the expression of PI3K, PKC, COX‐2, and ROS Enhances the expression of p53 and BAX Maurya and Vinayak (2015) Activates p53‐ROS crosstalk and induces epigenetic modifications Bishayee, Khuda‐Bukhsh, and Huh (2015) Triggers BCL2/BAX‐mediated apoptosis, as well as necrosis and mitotic catastrophe Inhibits the migratory potential of A549 cells Klimaszewska‐Wiśniewska et al. (2017) Inhibits aurora B activities Reduces the phosphorylation of histone 3 Xingyu et al. (2016) Chuang et al. (2016) and Warnakulasuriya, Ziaullah, Enhances expressions of nm23‐H1 and tissue inhibitor of and Rupasinghe (2016) metalloproteinase Inhibits the protein expression of MMP‐2. GW9662, a PPAR‐γ antagonist Prostate cancer Increases miR‐21 expression and causes inhibition of PDCD4 induced by [Cr(VI)] Pratheeshkumar et al. (2017) Decreases tumor improvement, down‐regulates Ki67, and enhances caspase 7 Down‐regulates growth factors such as VEGF and EGF Sharma et al. (2016), P. Wang, Henning, et al. (2016), and Y. Wang, Zhang, et al. (2016) Prevents TGF‐β‐induced expression of vimentin and N‐cadherin Decreases TGF‐β‐induced expression of Twist, Snail, and Slug in prostate cancer‐3 cell line Baruah, Khandwekar, and Sharma (2016) (Continues) RAUF 4 TABLE 1 ET AL. (Continued) Cancer types Mechanisms References Bladder cancer Inhibits cell proliferation and colony formation of human bladder cancer cells by inducing DNA damage Oršolić et al. (2016) Gastric cancer Inhibits EBV viral protein expressions, including EBNA‐1 and LMP‐2 proteins Prompts p53‐subordinate apoptosis Induces the expression of p53, Bax, and Puma Cleaves caspase‐3 and ‐9 and Parp J. Lee, Lee, Kim, et al. (2016) and H. H. Lee, Lee, Shin, et al. (2016) Causes mitochondrial apoptotic‐dependent growth inhibition via the blockade of PI3K‐Akt signaling Activates caspase‐3 and ‐9 Down‐regulates the Bcl‐2 and up‐regulates the Bax and cytochrome c Causes mitochondrial apoptotic‐dependent growth inhibition via the blockade of PI3K‐Akt signaling Shen et al. (2016) Decreases cyclin D1 expression in SKOV3 and U2OSPt cells Catanzaro, Ragazzi, Vianello, Caparrotta, and Montopoli (2015) Inhibits 143B proliferation and up‐regulates the expression of miR‐217 X. Zhang, Guo, et al. (2015), J. Y. Zhang, Lin, et al. (2015), and X. A. Zhang, Zhang, et al. (2015) Bone cancer Blood cancer F. Y. Chen, Cao, et al. (2015), X. Chen, Dong, et al. Activates caspase‐3, ‐8, and ‐9 and promotes leukemic cell apoptosis (2015), and Q. Chen, Li, et al. (2015) Reduced expression of the antiapoptotic proteins B‐cell, lymphoma (Bcl)‐2. Enhances expression of the proapoptotic proteins Bcl‐2‐interacting mediator of cell death Brain cancer Suppresses COX‐2 expression by Hsp27 inhibition and acts as both COX‐2 Q. C. Li, Liang, Hu, and Tian (2016) and J. Li, Tang, Li, Li, and Fan (2016) and Santos et al. (2015) Hsp27 inhibitor Reduces MMP‐2 expression Decreases mitochondria and rough endoplasmic reticulum injury Reduces filopodia‐like structures on the cell surface Head and neck cancer Cervical cancer Skin cancer Induces necrotic cell death and down‐regulates the Bcl‐2 mRNAs expression. Enhances mitochondrial mRNAs expression Modulates the mitochondrial pathway and the JAK2/STAT3 signaling Wang et al. (2013) Retards colony growth of HSC‐3 cells Suppresses the MMP‐2 and MMP‐9 Chan, Lien, Lee, and Huang (2016) Causes cells arrest at the G1 phase Induces apoptosis, suppresses the expression of Bax, and activates the expression of Caspase‐3 and Bcl‐2 Reverses gene‐encoded Pglycoprotein‐mediated MDR Z. Yuan et al. (2015) Inhibits antiapoptotic AKT and Bcl‐2 expression Increases mitochondrial cytochrome‐c level Causes cell cycle arrest at G2/M Bishayee et al. (2013) Induces apoptosis via PI3k/Akt pathways Xiang, Fang, and Wang (2014) Significantly inhibits UBE2S expression Lin et al. (2017) Blocks UVB irradiation‐induced COX‐2 up‐expression and NF‐kB activation in Hacat cell line Caddeo et al. (2016) Ali and Dixit (2015) Reduces the tumor size and the cumulative number of papillomas. Decreases the serum levels of glutamate oxalate transaminase, glutamate pyruvate transaminase, alkaline phosphatase, and bilirubin Inhibits PI3K and MAPK signaling Attenuates MEK–ERK signaling and influences PI3K/Akt pathway Rafiq et al. (2015) Eye cancer Decreases dose‐dependently the RPE cell proliferation, migration, and secretion of VEGF Inhibits the secretion of VEGF evoked by CoCl2‐induced hypoxia R. Chen et al. (2014) Thyroid cancer Lowers the cell proliferation and increases rate of apoptosis by caspase activation Downregulates the levels of Hsp90 Decreases chymotrypsin‐like proteasome activity Mutlu Altundağ et al. (2016) and Quagliariello et al. (2016) Ovarian cancer Suppresses ROS‐induced injury and increases the expression of endogenous antioxidant enzymes W. Li, Liu, et al. (2014), N. Li, Sun, et al. (2014), X. Li, Wang, et al. (2014), and W. Li, Zhao, et al. (2014) (Continues) RAUF ET AL. 5 (Continued) TABLE 1 Cancer types Mechanisms References Induces apoptosis of A2780S cells and activates caspase‐3 and caspase‐9. Gao et al. (2012) Down‐regulates MCL‐1 and Bcl‐2. Up‐regulates Bax and changes mitochondrial transmembrane potential Kidney cancer Protects against DOX‐induced nephrotoxicity and enhances the cytotoxic Heeba and Mahmoud (2016) effects of DOX. Decreases renal expressions of TNF‐α, IL‐1B, iNOS, and caspase‐3 Mesothelioma cancer Modulates gene expression of cyclins and cyclin‐dependent kinases Up‐regulates JNK, p38, and MAPK/ERK pathways and enhances ERK phosphorylation Demiroglu‐Zergeroglu, Ergene, Ayvali, Kuete, and Sivas (2016) Note. BT: breast tumor; EGF: epidermal growth factor; NQO1: NAD(P)H quinone oxidoreductase 1; MRP1: multidrug resistant protein 1; GADD45: growth arrest and DNA damage‐inducible 45; JAK1: Janus kinase 1; FAK: focal adhesion kinase; PKC: protein kinase C; iNOS: inducible nitric oxide synthase; UBE2S: ubiquitin E2S ligase; RPE: retinal pigment epithelial; STAT3: signal transducer and activator of transcription 3. FIGURE 2 Anticancer role of quercetin. Bax: Bcl‐2‐associated X protein [Colour figure can be viewed at wileyonlinelibrary.com] formation, and impeded tumor growth and metastasis of the breast and clonogenic survival of breast tumor‐474 cells as a function of dose cancer pathway and time. This might be accompanied by an increase in sub‐G0/G1 (Balakrishnan et al., 2016; Quagliariello et al., 2016). Quercetin also apoptotic populations. Quercetin could also induce up‐regulation of causes cell cycle arrest and apoptosis in breast cancer cells via modu- the levels of cleaved caspase‐8 and cleaved caspase‐3 (caspase‐ lating Akt and Bcl‐2‐associated X protein (Bax) signaling mechanistic dependent extrinsic apoptosis) and causing the cleavage of pathways (Sarkar et al., 2016). The administration of quercetin at poly(ADP‐ribose)polymerase (PARP). However, it did not induce apo- 15 μM suppressed the breast cancer cell proliferation by inducing apo- ptosis via intrinsic mitochondrial apoptosis pathway and did not affect ptosis, assuring cell cycle arrest, and attenuating the tumor growth the levels of Bcl‐2 and Bax. Quercetin was also found to suppress the cells through the EGFR/VEGFR‐2 signaling (Rivera, Castillo‐Pichardo, Gerena, & Dharmawardhane, 2016). expression of phospho‐Janus kinase 1 (JAK1) and phospho‐signal Balakrishnan and colleagues have recently evaluated the effects of transducer and activator of transcription 3 (STAT3) and attenuates gold nanoparticles–conjugated quercetin (AuNPs‐Qu‐5) in MCF‐7 STAT3‐dependent luciferase reporter gene activity (breast tumor‐ and MDA‐MB‐231 breast cancer cell lines. These researchers showed 474 cells; Seo et al., 2016). In a similar fashion, quercetin inhibits the that the administration of AuNPs‐Qu‐5 inhibits cell proliferation in activity and expression of P‐glycoprotein and causes a significant breast cancer cell lines through induction of apoptosis and suppresses reduction in Dox resistance in MCF‐7/ADR breast cancer cells (Lv EGFR signaling. In addition, treatment with these nanoparticles up‐ et al., 2016). In female BALB/c nude mice, it has attenuated tumor regulated the proapoptotic proteins (Bax, Caspase‐3) and down‐regu- growth, oncocyte proliferation, and tumor necrosis. It has also modu- lated antiapoptotic protein (Bcl‐2). Collectively, these AuNPs‐Qu‐5 lated serum VEGF and markedly reserved tumor calcineurin activities. particles could be a potential drug delivery system in breast cancer Additionally, it has down‐regulated gene expression of VEGF and therapy (Balakrishnan et al., 2017). reduced protein levels of VEGF (X. Zhao et al., 2016). Adrenaline In a recent investigation, Seo and colleagues have evaluated the and noradrenaline (endogenous catecholamines) are secreted by adre- effect of quercetin on the proliferation and apoptosis in breast cancer nal gland and sympathetic nervous system on exposure to stress. The cells. These researchers found that quercetin reserves the proliferation adrenergic system plays an important role in stress signaling, where RAUF 6 ET AL. excessive stress can be linked to increased production of reactive oxy- The anti‐toll‐like receptor 4 (TLR4) antibody of pyrrolidine dithio- gen species (ROS). Overproduction of ROS induces oxidative damage carbamate might influence the inhibition of quercetin on cell migration and causes the development of diseases such as cancer. Research and invasion and the expression of various proteins such as E‐ findings revealed that quercetin suppresses (a) generation of ROS, (b) cadherin, MMP‐2, MMP‐9, NF‐κB p65, and TLR4. Moreover, querce- activation of cyclic adenosine monophosphate and reticular activating tin could lessen the production of different inflammation factors system (RAS), and (c) phosphorylation of extracellular signal‐regulated including TNF‐α, Cox‐2, and interleukin 6 (IL‐6). Hence, quercetin kinases 1/2 (ERK1/2) and the expression of HMOX1, MMP‐2, and might exert its anti‐colon cancer activity via the TLR4‐ and/or MMP‐9 genes. It also suppresses invasion of breast cancer cells by NF‐κB‐mediated signaling pathway (M. Han et al., 2016). The 1,2‐ controlling β2‐adrenergic signaling (Yamazaki, Miyoshi, Kawabata, dimethyl hydrazine‐induced colon cancer causes nephrotoxicity Yasuda, & Shimoi, 2014). The (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphe- and further increases the blood urea nitrogen, urea, creatinine, and nyltetrazolium bromide) assay has recently been used to investigate eventually result in a number of aberrant crypts and foci formation. the anticancer effect of quercetin and its underlying mechanisms in The potential protective effect of quercetin on cisplatin‐induced triple‐negative breast cancer cells. Results indicated that quercetin nephrotoxicity was assessed through lowing the blood urea nitro- increases cell apoptosis, inhibits cell cycle progression, and increases gen, urea, and creatine and also reduced the aberrant crypt foci FasL mRNA expression and p51, p21, and growth arrest and DNA number (Q. C. Li, Liang, et al., 2016; J. Li, Tang, et al., 2016). Similar damage‐inducible 45 (GADD45) signaling activities. These results sug- results were obtained by Saleem et al. (2015) who found that treat- gest that quercetin induces apoptosis and cell cycle arrest via modifi- ment of mice either with quercetin, sodium gluconate, or with the cation of Foxo3a signaling in triple‐negative breast cancer cells combination has a positive effect against 1,2‐dimethyl hydrazine‐ (Nguyen et al., 2017). induced colon cancer. In human colon adenocarcinoma cells, quercetin significantly enhanced the expression of the endocannabinoids receptor (CB1‐R) 2.2 | Colon cancer and further suppressed PI3K/Akt/mTOR. It also induced JNK/JUN pathways and modified the metabolism of β‐catenin, either directly Diet is an important factor associated with colon cancer. Diets that are or via activation of CB1‐R (Refolo et al., 2015). These findings were low in fiber and high in fat, calories, and red meat and processed meats confirmed by other researchers (Xu et al., 2015). The research work increase the risk of developing colon cancer. Cancer treatment conducted by Zhang et al. indicated that quercetin significantly pre- depends on the type of cancer, the stage of the cancer (how much it vents the proliferation of human colon cancer in CACO‐2 and SW‐ has spread), age, health status, and additional personal characteristics 620 cells by suppressing the NF‐κB pathway, down‐regulation of B‐ (NCI, 2014). cell lymphoma 2, and up‐regulation of Bax (X. Zhang, Guo, Chen, & Numerous studies have dealt with the effect of quercetin on Chen, 2015; J. Y. Zhang, Lin, et al., 2015; X. A. Zhang, Zhang, Yin, & colon cancer. Kee and coworkers used the water‐soluble tetrazolium Zhang, 2015). In addition, quercetin was found to have an inhibitory salts assay, annexin V assay, real‐time polymerase chain reaction, effect on Wnt/β‐catenin in colon cancer cells SW480, DLD‐1, and western blot analysis, and gelatin zymography to study the inhibitory HCT116 cancer cells (Amado et al., 2014). Similarly, a study by Kim effect of quercetin on colorectal lung metastasis. These researchers et al. demonstrated that the inhibitory role of quercetin in colon can- found that quercetin can (a) inhibit the cell viability of colon 26 cer cell lines through enhancing the apoptotic cell death via generating (CT26) and colon 38 (MC38) cells, (b) induce apoptosis through the intracellular ROS and through enhancing sestrin 2 expression is MAPKs pathway in CT26 cells, (c) regulate the expression of EMT accompanied by markers, such as E‐, N‐cadherin, β‐catenin, and snail, by nontoxic con- Moreover, these researchers found that the quercetin‐induced apo- centrations of quercetin, and (d) inhibit the migration and invasion ptosis involves sestrin 2/AMPK/mTOR pathway by regulating abilities of CT26 cells through expression of MMPs and tissue inhibi- increases intracellular ROS (Kim, Lee, & Kim, 2013; Kim, Moon, Ahn, tor of metalloproteinases (TIMPs) regulation. They concluded from & Cho, 2013). activated protein kinase (AMPK) activation. this investigation that quercetin can inhibit the survival and metastatic For HT‐29 colon cancer cells, Kim and coworkers found that quer- ability of CT26 cells, and can suppress colorectal lung metastasis in the cetin induces apoptosis by attenuating membrane potential of the mouse model, and may be a potent therapeutic agent for the treat- mitochondria producing intracellular ROS and elevating the expression ment of metastatic colorectal cancer (Kee et al., 2016). Similarly, an of sestrin 2 via the AMPK/p38 mechanistic pathway (G. T. Kim, Lee, investigation by Zhao et al. concluded that 8‐C‐(E‐phenylethenyl) Kim, & Kim, 2014; M. C. Kim, Lee, Lim, et al., 2014). Similarly, several quercetin, a novel quercetin derivative, triggers G2 phase arrest in research groups independently showed that quercetin increases the colon cancer cells and suppresses propagation. It also induces autoph- antioxidant activity, increases PARP cleavage, and induces caspase‐ agic cell death through ERK stimulation (Y. Zhao, Fan, et al., 2017; J. 3‐cleavage (twofold) in HT‐29 colon cancer cells. It also lowers the Zhao, Liu, et al., 2017). Similarly, quercetin at a concentration of expressions of specificity proteins (Sp) such as Sp1, Sp3, and Sp4 5 μM could markedly suppress the migratory and invasive capacity mRNA; this expression was accompanied by a decreased protein of Caco‐2 cells. In addition, results from this investigation revealed expression. In addition, the Sp‐dependent antiapoptotic survival gene that the expression of E‐cadherin protein was increased by quercetin, was also significantly decreased, both at mRNA and protein levels. It whereas metastasis‐related proteins of MMP‐2, MMP‐9 expression also attenuates microRNA‐27a and induces a Sp‐repressor, zinc finger got decreased by it in a dose‐dependent manner. protein ZBTB10 (Atashpour et al., 2015; Cho, Kim, Park, Choo, & RAUF ET AL. 7 Chong, 2013; Del Follo‐Martinez, Banerjee, Li, Safe, & Mertens‐ condensation, and sub‐G0/G1 fraction of cell cycle increase. It also Talcott, 2013). increases the buildup of intracellular Ca2+ ions and Grp78/Bip and GADD153/CCAAT enhancer‐binding protein homologous protein 2.3 | Pancreatic cancer (CHOP) protein expression and triggers mitochondrial dysfunction. Quercetin exerts this cytotoxicity against human pancreatic cancer Research revealed that quercetin induces apoptosis in tumor necrosis cells trough endoplasmic reticulum stress‐mediated apoptotic signal- factor‐related apoptosis‐inducing ligand (TRAIL) in resistant pancreatic ing including pathway, as well as ROS production and mitochondrial cancer cells. It was also found that a BH3‐only protein BID consider- dysfunction (J. H. Lee et al., 2013). Other researchers found that quer- ably reduces attenuated TRAIL/quercetin‐induced apoptosis. Querce- cetin exerts its antiproliferative effects in pancreatic cancer cells by tin has also the ability to reduce the expression levels of cellular inducing apoptosis and attenuating the growth of orthotopically FLICE‐like inhibitory protein and to strongly save pancreatic cancer transplanted pancreatic xenografts (Angst et al., 2013). In MIA PaCa‐ cells from TRAIL/quercetin‐induced apoptosis, in a dose‐dependent 2 pancreatic adenocarcinoma cells, quercetin at 100 μM inhibits tracer manner. Additionally, quercetin stimulates JNK, which influences the glucose‐derived glycogen labeling (Σm), slows down glycogen synthe- proteasomal degradation of cellular FLICE‐like inhibitory protein, sis, and manages tumor cell proliferation (Harris et al., 2012). followed by sensitized pancreatic cancer cells to TRAIL‐induced apoptosis (J. H. Kim et al., 2016; Nwaeburu et al., 2016). In human pancreatic cancer cell lines CFPAC‐1 and SNU‐213, quercetin‐3‐O‐glucoside 2.4 | Liver cancer suppresses the migratory activity induced by transforming growth fac- The leading cause of liver cancer is cirrhosis due to either hepatitis B, tor‐beta (TGF‐β) and vascular endothelial growth factor A even at rel- hepatitis C, or excess alcohol intake (Naghavi, Wang, Lozano, et al., atively low dosages in CFPAC‐1, but not in bFGF‐activated SNU‐213 2015). Other causes include aflatoxin, nonalcoholic fatty liver disease, cells. In addition, co‐treatment with low dose of gemcitabine and and liver flukes. The most common types are hepatocellular carci- quercetin‐3‐O‐glucoside exhibited synergistic inhibition effects on noma, which makes up to 80% of cases, and cholangiocarcinoma the infiltrate activity induced by bFGF in CFPAC‐1 and SNU‐213 cells (NCI, 2016). (J. Lee, Lee, Kim, & Kim, 2016; H. H. Lee, Lee, Shin, et al., 2016). Previous studies demonstrated that treatment with nano‐capsu- Cao et al. demonstrated that quercetin in combination with lated quercetin restricts all changes in diethyl nitrosamine‐mediated gemcitabine suppresses proliferation, invasion and self‐renewal capac- development of hepatocarcinogenesis, suggesting that this nano‐cap- ity, and cancer stem cells surface markers expression, with alterations sulated natural product may be accepted as a potent therapeutic agent of β‐catenin in pancreatic cancer stem‐like cells. In addition, it reduces in preventing diethyl nitrosamine‐mediated hepatocarcinogenesis tumor growth and drug resistance in pancreatic cancer (Cao et al., (Mandal et al., 2014). In addition, fatty acid esters of quercetin‐3‐O‐ 2015). In a similar fashion, Lee et al. found that quercetin suppresses glucoside were found to exhibit significant inhibition of HepG2 cell epidermal growth factor‐induced migration activity and inhibits the proliferation. Effect of this novel compound was associated with cell infiltration activity of pancreatic cancer cells in a dose‐dependent ycle arrest in S‐phase and apoptosis. Furthermore, quercetin‐3‐O‐glu- manner in human pancreatic cancer cell lines. Furthermore, these coside esters showed significant low toxicity to normal liver cells than researchers found that antitumor effects of quercetin are mediated sorafenib, a chemotherapy drug used in the treatment of hepatocellu- by selectively inhibiting the EGFR‐mediated focal adhesion kinase, lar carcinoma (Sudan & Rupasinghe, 2015). Treatment with quercetin protein kinase B (AKT), MEK1/2, and ERK1/2 signaling pathway (J. at a dose of 50 mg/kg in mice showed a protective effect on cis- Lee, Han, Yun, & Kim, 2015; W. J. Lee, Hsiao, et al., 2015; Y. J. Lee, platin‐induced DNA damage in normal cells, without interfering with Lee, & Lee, 2015; S. H. Lee, Lee, Min, et al., 2015). Similarly, quercetin the antitumor efficacy of the combined treatment. These results sug- significantly inhibits proliferation, promotes apoptosis, and induces cell gest that quercetin can protect the blood, liver, and kidney cells of cycle arrest within the G1 phase in pancreatic cancer cells. It can also mice against HIPEC‐induced injury and can increase survival of mice activate caspase‐3, ‐8, and ‐9 and reduces the mitochondrial mem- by improving the antitumor adaptive immunity with hyperthermia brane potential and can inhibit the expression level of the δ opioid (Oršolić & Car, 2014). receptor, whereas isoquercitrin was found to have no effect on the κ Quercetin inhibits the growth of cancer cells, which can be attrib- and μ opioid receptors. Furthermore, quercetin can inhibit ERK phos- uted to various mechanisms, such as the induction of cell cycle arrest phorylation, promote JNK phosphorylation, and significantly inhibit and/or apoptosis, as well as its antioxidant functions. In this respect, xenograft growth in nude mice (F. Y. Chen, Cao, et al., 2015; X. Chen, Zhao and coworkers evaluated the activity of quercetin in human liver Dong, et al., 2015; Q. Chen, Li, et al., 2015). cancer HepG2 cells. These workers found that quercetin can induce On the other hand, research conducted by Appari and coworkers apoptosis in human liver cancer HepG2 cells with overexpression of revealed that quercetin significantly inhibits viability, migration, fatty acid synthase. These results suggest that apoptosis is induced expression of MMP‐2 and ‐9, aldehyde dehydrogenase 1 activity, col- by quercetin via the inhibition of fatty acid synthase. Additionally, ony, and spheroid formation and triggers apoptosis in pancreatic duc- findings by these researchers suggest that quercetin may be useful tal adenocarcinoma. It also induces the expression of miR‐let7‐a and for preventing human liver cancer (P. Zhao et al., 2014). Furthermore, causes inhibition of K‐ras in cancer cells (Appari, Babu, Kaczorowski, it was demonstrated by a number of researchers that intake of querce- Gross, & Herr, 2014). Similarly, it induces apoptosis of PANC‐1, char- tin seems to play a minor regulatory role, whereas supplement doses acterized as nucleic acid and genomic DNA fragmentation, chromatin may have great effects on gene expression in hepatocytes. Further RAUF 8 ET AL. work is certainly required in handling of quercetin supplements human lung carcinoma A549 cells, researchers demonstrated that (Waizenegger et al., 2015a). quercetin appreciably suppresses cell invasion and migration. It Controlled release of medications remains the most convenient inhibits the activity and expression of MMPs‐2 in a dose‐dependent way to deliver drugs. Bishayee and coworkers examined the effect manner. It also increases the expressions of nm23‐H1 and TIMP‐2 of gold‐quercetin loaded into poly(DL‐lactide‐co‐glycolide) nanoparti- and inhibits the protein expression of MMP‐2. GW9662, a PPAR‐γ cles (NQ) on HepG2 hepatocarcinoma cells. Results revealed that antagonist (Chuang et al., 2016; Warnakulasuriya et al., 2016). quercetin loaded on the nanoparticles preferentially kill cancer cells, In their work on lung carcinogenesis, Chen and colleagues demon- compared with normal cells. In addition, NQ interacted with HepG2 strated that benzo[a]pyrene‐induced human bronchial epithelial cell cell DNA and reduces histone deacetylases to manage cell prolifera- (HBEC) transformation is improved by IL‐6 in vitro. The carcinogen/ tion and arrest the cell cycle at the sub‐G stage. These nanoparticles IL‐6‐transformed cells exhibit higher expression of signal transducer induce apoptosis in HepG2 cells by activating p53‐ROS crosstalk and and activator of STAT3 when compared with cells transformed by by enhancing epigenetic modifications leading to inhibited prolifera- BPDE alone. Furthermore, these researchers showed that treatment tion and cell cycle arrest (Bishayee et al., 2015). Protein kinase C is a with quercetin (a) considerably decreases BPDE‐stimulated IL‐6 secre- key regulator of cell growth in mammalian cells and is linked with tion from human lung fibroblasts via inhibition of the NF‐κB and ERK tumor succession. Quercetin, on the other hand, exhibits antitumor pathways, (b) blocks IL‐6‐induced STAT3 activation in HBECs, and (c) activity both in vitro and in vivo in HepG2 cells. It down‐regulates abolishes IL‐6 enhancement of HBEC transformation by BPDE (W. the expression of PI3K, protein kinase C, COX‐2, and ROS. Addition- Chen et al., 2016). On the other hand, Zhao and coworkers examined ally, it enhances the expression of p53 and BAX in HepG2 cells the inhibitory effect of quercetin on the growth of A549 lung cancer (Maurya & Vinayak, 2015). One of the shortcomings of quercetin in cells and found that it induces apoptosis, decreases the levels of clinics is its poor solubility. To overcome these disadvantages, Guan MMP‐9 (mRNA and protein) and TGF‐β1 protein, and reduces the and coworkers prepared quercetin (QT) as QT‐loaded PLGA‐TPGS number of tumor cells. These researchers also found that the combi- nanoparticles (QPTN) and evaluated its therapeutic efficacy for liver nation of quercetin (at low concentrations) with TIMP‐1 shows syner- cancer. Results indicated that QPTN could induce HepG2 cell apopto- gistic inhibitory effect on the growth of A549 cells (X. Zhao & Zhang, sis in a dose‐dependent manner and that QPTN could suppress tumor 2015). Quercetin also decreases claudin‐2 expression in lung adeno- growth by 59.07%. These researchers concluded that QPTN could be carcinoma A549 cells in a time‐ and concentration‐dependent manner, used as a potential intravenous dosage form for the treatment of liver lowers the stability of claudin‐2 mRNA, and increases the expression cancer owing to the enhanced pharmacological effects of quercetin of miR‐16. Categorically, quercetin reduces claudin‐2 level through with increased liver targeting (Guan et al., 2016). up‐regulation of miR‐16 expression (Sonoki et al., 2015). In lung cancer cells (A549 and H460 cells), quercetin reduced cell viability and 2.5 | Lung cancer Several research papers have dealt with quercetin as a chemothera- inhibited heat shock protein 70 (HSP70) expression in both cell lines in a dose‐dependent manner. Addition of a fixed quercetin dose improved gemcitabine‐induced cell death, which was linked to peutic agent against lung cancer. An investigation by W. Chen, Wang, increased caspase‐3 and caspase‐9 activities (J. Lee, Han, et al., Zhuang, Zhang, and Lin (2007) revealed that quercetin significantly 2015; W. J. Lee, Hsiao, et al., 2015; Y. J. Lee, Lee, & Lee, 2015; S. enhances TRAIL‐induced cytotoxicity in non‐small cell lung cancer H. Lee, Lee, Min, et al., 2015; Y. Liu, Wu, & Zhang, 2015). cells. It also increases expression of death receptor (DR) 5 and has Similarly, quercetin prevented tumor proliferation by (a) initiating no effect on other components of the death‐inducing signaling com- cell cycle arrest, (b) improving TRAIL‐induced tumor cell death, (c) low- plex. In addition, these researchers demonstrated that quercetin can ering the p62 protein expression, and (d) increasing GFP‐LC3B in sensitize TRAIL‐induced cytotoxicity in lung cancer cells via two mech- human lung cancer cells in a dose‐dependent fashion (Moon, Eo, anisms: (a) by induction of DR5 and (b) by suppression of survivin Lee, & Park, 2015; J. Wang, Zhang, Cheng, Zhang, & Li, 2015). It also expression; these mechanisms may explain the lung cancer preventive induces apoptosis in A549 cells via mitochondrial depolarization by activity of quercetin. Furthermore, researchers found that treatment triggering an imbalance in B‐cell lymphoma 2/Bcl2 antagonist X of human lung cancer H‐520 cells with quercetin increases the cis- (Bcl2/Bax) ratio and by down‐regulating the IL‐6/STAT3 signaling platin‐induced apoptosis by 30.2%, down‐regulates Bcl‐XL and Bcl‐2, pathway. Additionally, quercetin could block nuclear factor kappa‐ and up‐regulates Bax (Kuhar, Sen, & Singh, 2006). light‐chain‐enhancer of activated B cells (NF‐κB) action at early hours, For JB6 Cl41 cells and A549 lung cancer cells, researchers which might cause a down‐regulation of the IL‐6 titer, and the IL‐6 showed that quercetin inhibits aurora B activities and reduces the expression, in turn, could inhibit p‐STAT3 expression. Down‐regula- phosphorylation of histone 3 (Xingyu et al., 2016). Quercetin also tion of both the STAT3 and NF‐κB expressions might, consequently, reduces ROS production induced by exposure to hexavalent chro- causes down‐regulation of Bcl2 because both are upstream effectors mium [Cr(VI)] in BEAS‐2B cells. It also suppresses the malignant cell of Bc12. In A549 cells, modification in Bcl2 reactions may result in transformation, improves miR‐21 expression, and causes inhibition of an imbalance in the Bcl2/Bax ratio, which could eventually lead mito- PDCD4 induced by [Cr(VI)] in a dose‐dependent manner. Further- chondria mediated apoptosis (Mukherjee & Khuda‐Bukhsh, 2015). more, quercetin reduces the tumor occurrence and suppresses the Nair and colleagues examined the cumulative effects of curcumin Cr(VI)‐induced malignant transformation and tumorigenesis in nude and quercetin in inducing apoptosis in benzo(a)pyrene (100 mg/kg mice injected with BEAS‐2B cells (Pratheeshkumar et al., 2017). In body weight)‐induced lung carcinogenesis in mice. In benzo(a) RAUF ET AL. 9 pyrene‐treated animals, supplementation of curcumin (60 mg/kg body natural compounds have the potential for use as chemopreventive weight) and quercetin (40 mg/kg body weight), separate as well as agents of androgen resistance in prostate cancer (Sharma et al., 2016). combined, considerably reduced the protein expression of Bcl‐2 and The therapeutic potential of novel quercetin‐loaded nanomicelles amplified the protein expression of Bax. Supplementation also (to enhance the solubility of quercetin in water) for prostate cancer improved the enzyme activities of caspase 9 and caspase 3 (Nair, treatment was recently evaluated. Results indicated that quercetin Malhotra, & Dhawan, 2015). In addition, a peer group of investigators can be efficiently encapsulated into micelles up to 1 mg per ml, which (Lam et al., 2012; Youn, Jeong, Jeong, Kim, & Um, 2013) determined corresponds to a 450‐fold increase of its water solubility. Additionally, that quercetin strongly inhibits cell production and enhanced sub‐G1 a nanomicelle‐based drug delivery system could be a promising and and apoptosis despite of p53 status in H460 cells. It also improved effective therapeutic strategy for clinical treatment of prostate cancer the expression of genes linked with DR signaling TRAIL receptor, cas- (X. Zhao et al., 2016). In LNCaP and PC‐3 cells, Song et al. examined pase‐10, IL 1R DNA fragmentation factor 45, tumor necrosis factor the effects of quercetin combined with 2‐methoxyestradiol on the receptor 1, FAS, inhibitor of kappa‐B‐alpha (IκBα), and cell cycle inhi- proliferation of androgen‐dependent LNCaP and androgen‐indepen- bition GADD45, p21 (Cip1). However, it reduced the expression of dent PC‐3 human prostate cancer cells lines. Both quercetin and 2‐ genes involved in activation of NF‐κB and IKKα. It also suppressed methoxyestradiol could inhibit the growth of prostate cancer cells in the NF‐κB and additionally improved the expression of DRs and cell a dose‐dependent manner. In addition, different concentrations of cycle inhibitors (Lam et al., 2012; Youn et al., 2013). In A549 non‐small quercetin ranging from 0 to 200 μmol/L suppress the growth rates cell lung cancer cells, Klimaszewska‐Wiśniewska and colleagues have of LNCaP and PC‐3 cells by inducing apoptosis and triggering cell recently employed the methyl‐thiazol‐diphenyl‐tetrazolium (MTT) cycle arrest (Song, Wang, Wang, & Xing, 2016). Unmistakably, querce- assay, annexin V/propidium iodide test, electron microscopic examina- tin induces apoptosis, which leads to cytochrome c release, cleavage tion, cell cycle analysis based on DNA content, real‐time polymerase of caspase 3, and PARP. Quercetin also impedes generation of ROS chain reaction assays, in vitro scratch wound‐healing assay, fluores- and Akt/mTOR cell survival pathways in PC‐3 cells (Hamidullah et al., cence staining of F‐actin, β‐tubulin, and vimentin to examine the 2015; Paller et al., 2015). The hyperoside and quercetin in blend effect of quercetin on microfilaments, microtubules, and vimentin inhibited the development of prostate cancer cells. It induced apopto- intermediate filaments. Results revealed that quercetin triggers sis, cell cycle arrest, and reduced invasive capacity, through inhibition BCL2/BAX‐mediated apoptosis, necrosis, and mitotic catastrophe of the miR‐21 signaling pathway (F. Q. Yang, Liu, Li, et al., 2015; Z. and suppresses the migratory potential of A549 cells. These findings Yang, Liu, Liao, et al., 2015; F. Yang, Song, et al., 2015). suggest that quercetin‐induced mitotic catastrophe involves the per- In LAPC‐4‐AI and PC‐3 prostate cancer cells, quercetin at a con- turbation of mitotic microtubules, which results in monopolar spindle centration of 5 μM significantly enhanced cell cycle arrest at G2/M formation and to failure of cytokinesis (Klimaszewska‐Wiśniewska phase and increased apoptosis. Quercetin also increased the inhibition et al., 2017) of PI3K/Akt and the STAT3 signaling pathways compared with Doc alone and decreased the protein expression of multidrug resistance‐ 2.6 | Prostate cancer related protein (Y. Wang, Han, et al., 2015; P. Wang, Henning, Heber, & Vadgama, 2015; P. Wang, Phan, et al., 2015; J. Wang, Zhang, Cheng, Numerous researchers have investigated the effect of quercetin, alone Zhang, & Li, 2015). Y. Wang, Han, et al. (2015), P. Wang, Henning, or in combination with other drugs, on colon cancer. Standard treat- et al. (2015), P. Wang, Phan, et al. (2015) and J. Wang, Zhang, et al. ment for metastatic and castration‐resistant prostate cancer includes (2015) evaluated the effect of a combination of arctigenin and querce- chemotherapy with docetaxel (Doc). However, chemoresistance and tin, two promising natural chemo‐preventive agents, on Androgen‐ side effects of Doc limit its clinical success. In this respect, different dependent LAPC‐4 and LNCaP prostate cancer cells. Results from this research groups investigated the effect of natural products such as investigation revealed that the combination of the aforementioned quercetin on the efficacy of androgen‐independent prostate cancer compounds inhibits both androgen receptor and PI3K/Akt pathways. cells. These researchers found that quercetin (a) improves the healing In addition, results showed that the mixture inhibitions cell migration practicality of Doc, (b) considerably lessens tumor progression, (c) cut in both cell lines compared with individual compounds tested (Y. down the Ki67, (d) increases cleavage of caspase 7, (e) lowers blood Wang, Han, et al., 2015; P. Wang, Henning, et al., 2015; P. Wang, concentrations of growth factors, such as VEGF and epidermal growth Phan, et al., 2015; J. Wang, Zhang, et al., 2015). In androgen‐depen- factor, and (f) substantially lifts the levels of tumor silencer mir15a and dent LNCaP and androgen‐independent PC‐3 human prostate cancer mir330 (P. Wang, Henning, et al., 2016; Y. Wang, Zhang, Lv, Zhang, & cell lines of male BALB/c nude, the inhibitory effect of a combination Zhu, 2016). In castration‐resistant prostate cancer cells, quercetin of quercetin and 2‐methoxyestradiol was investigated. Results improves the therapeutic effect of Doc in through multiple mecha- showed that the combination appreciably inhibits prostate cancer nisms including down‐regulation of chemoresistance‐related proteins xenograft tumor growth for both cell lines as compared with control, (P. Wang, Henning, et al., 2016; Y. Wang, Zhang, et al., 2016). Addi- which suggests that the combination can serve as a novel clinical tionally, in PC3 and DU145 prostate cancer cell lines, a combined treatment regimen for prostate cancer (F. Q. Yang, Liu, Li, et al., treatment with quercetin and curcumin, two known dietary 2015; Z. Yang, Liu, Liao, et al., 2015; F. Yang, Song, et al., 2015). phytocompounds with described DNMT‐inhibitory activity, was much Finally, a review by Baruah et al. (2016) concluded that quercetin more effective than either of them in both inhibition of DNMT and in can prevent TGF‐β‐induced expression of vimentin and N‐cadherin triggering apoptosis via mitochondrial depolarization. These two and expand the outflow of E‐cadherin in PC‐3 cells, along these lines RAUF 10 ET AL. forestalling TGF‐β‐initiated EMT. Besides, the relative expression of and Parp at comparative levels (J. Lee, Lee, Kim, et al., 2016; H. H. Twist, Snail, and Slug demonstrates that quercetin essentially dimin- Lee, Lee, Shin, et al., 2016). In gastric cancer stem cells, quercetin ishes TGF‐β‐induced expression of Twist, Snail, and Slug in PC‐3 cell induced cell apoptosis in a mitochondrial‐dependent approach line (Baruah et al., 2016). through (a) lessening in mitochondrial membrane potential, (b) enhancement of caspase‐3 and ‐9, (c) down‐regulation of Bcl‐2, and 2.7 | Bladder cancer (d) up‐regulation of Bax and cytochrome c. It, likewise, caused mitochondrial apoptotic‐dependent growth inhibition by diminishing the Bladder cancer is one of the most common cancers of the urinary tract PI3K‐Akt signaling and suppressed the overexpression of Bcl‐2 and and a major cause of cancer‐related mortality. Risk factors include kept the reduction in mitochondrial film potential. It similarly aug- smoking, occupational exposure to polycyclic aromatic hydrocarbons mented the levels of caspases, Bax, and cytochrome c (Shen et al., and aromatic amines, and, possibly, environmental pollution. On the 2016). In human gastric cancer MGC‐803 cells, X. Zhang, Guo, et al. other hand, fruits and vegetables intake may exert a protective effect (2015), J. Y. Zhang, Lin, et al. (2015), and X. A. Zhang, Zhang, et al. (Di Lorenzo et al., 2016 and references therein). The cytotoxic and (2015) demonstrated that a combined treatment with curcumin and genotoxic effects of quercetin on human bladder cancer T24 cells quercetin essentially suppresses cell multiplication, accompanied by have recently been investigated by Oršolić and colleagues by means loss of mitochondrial membrane potential (ΔΨm), release of cyto- of MTT test, clonogenic assay, and DNA damaging effect by comet chrome c and diminished phosphorylation of AKT and ERK. On the assay. These researchers showed that quercetin at doses of 1 and other hand, Kim and colleagues employed western blot analysis and 50 μM for introduction times (24, 48, and 72 hr) has cytotoxic and MTT assay to investigate the signaling pathway of quercetin‐induced genotoxic impacts on human bladder T24 cells. These results suggest apoptosis in the AGS cells, a commonly used human gastric adenocar- that quercetin may be an effective chemopreventive and chemothera- cinoma cell line. They found that quercetin exerts its effect against peutic agent and could prevent cell propagation and colony formation AGS cells through inducing apoptosis and suppressing the transient of human bladder cancer cells by expansion of DNA damage of T24 receptor potential melastatin (TRPM7) streams. Additionally, treat- cells (Oršolić et al., 2016). ment with quercetin extended the apoptosis of HEK293 cells, which Similarly, the role of autophagy in quercetin‐induced apoptosis in overexpress TRPM7. These researchers then concluded that quercetin human bladder carcinoma BIU‐87 cells in vitro was examined. Querce- might play an important pathophysiological role in AGS cells through tin considerably inhibited proliferation of BIU‐87 cells in a time‐ and MAPK signaling pathways and TRPM7 channels (G. T. Kim, Lee, Kim, dose‐dependent fashion and that autophagy is induced earlier than et al., 2014; M. C. Kim, Lee, Lim, et al., 2014). apoptosis. Hence, autophagy may play a protective role at the initia- In human gastric carcinoma, the EPG85‐257P cell line and its dau- tion phase by delaying apoptosis and reducing the quercetin‐induced norubicin‐resistant variation EPG85‐257RDB, quercetin exerted anti- death of BIU‐87 cells (Wei et al., 2012). Additionally, in bladder cancer proliferative impact (with an IC50 value of 12 μM after 72 hr), 253J cells, Y. Kim, Kim, and Cha (2011) found that large conductance predominantly through induction of apoptosis, abatement of P‐glyco- Ca2+‐activated K+ (BK(Ca)) or MaxiK channels are expressed and that protein expression, hindrance of medication transport, and down‐reg- quercetin increases BK(Ca) current in a concentration‐dependent and ulation of ABCB1 gene expression (Borska et al., 2012). Similarly, reversible manner. On the other hand, Su and coworkers have recently quercetin could inhibit the proliferation of human gastric cancer by examined the mechanisms of quercetin on inhibition of bladder can- down‐regulation of the expressions of leptin and leptin receptor pro- cer. They employed MTT and cologenic assays to test the inhibitory tein, leptin mRNA, and leptin receptor mRNA through the JAK–STAT sensitivity in vitro against two human and one murine bladder cancer pathway in MGC‐803 cells (Qin et al., 2012). cell lines and used western blot to examine AMPK pathway including In an effort to identify an effective drug as a potential candidate for 4E‐BP1 and S6K. These researchers found that quercetin induces apo- gastric cancer, Wang and colleagues investigated the effect of quercetin ptosis and inhibits migration via activation of AMPK (Su et al., 2016). on the apoptosis and morphology of gastric carcinoma BGC‐823 cells, as well as a plausible mechanism of action. Results indicated that quer- 2.8 | Gastric or stomach cancer cetin can induce apoptosis of the BGC‐823 cells, accompanied by a decrease in Bcl‐2/Bax ratio with increased expression of caspase‐3. A group of researchers have recently examined the anticancer effects This implies that quercetin‐induced apoptosis may be mediated through of quercetin and isoliquiritigenin in xenograft animals implanted with the mitochondrial pathway (K. Wang et al., 2011). Additionally, treat- Epstein–Barr virus (EBV)(+) or EBV(−) human gastric carcinoma. These ment of human gastric cancer cells MGC‐803 with quercetin at researchers found that quercetin exhibits anticancer effect in these 40 μmol/L considerably decreased the expression of VEGF‐C and cells by means of hindered EBV viral protein expressions, including VEGFR‐3 compared with the control group after 48 hr. This indicates EBNA‐1 and LMP‐2 proteins in tumor tissues from mice infused with that quercetin can down‐regulate the expression of VEGF‐C and EBV(+) human gastric carcinoma. Quercetin viably prompted p53‐ VEGFR‐3 in human gastric cancer cells MGC‐803 (Yu et al., 2009). dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this enlistment was related with expanded expressions of the separated types of caspase‐3, ‐9, and Parp. In EBV(−) human 2.9 | Bone cancer gastric carcinoma (MKN74), quercetin instigated the expressions of Osteosarcoma is becoming the most common malignant bone tumor p53, Bax, and Puma and the separated types of caspase‐3 and ‐9 in children and young adults. The main difficulties in osteosarcoma RAUF ET AL. 11 treatment are the occurrence of metastases, severe side effects, and effects of quercetin in U937 human leukemia cells (W. Chen et al., chemoresistance. Treatment of human osteosarcoma cell line 143B 2016). In BALB/c nude mice of P388 leukemic cells, quercetin and with quercetin substantially caused growth inhibition, G2/M phase the antileukemic drug Adriamycin could significantly extend the sur- arrest, and prompted apoptosis (Berndt et al., 2013). Quercetin vival of mice. Quercetin additionally might decrease the ratio of G0/ blocked the extension of human methotrexate safe osteosarcoma cell G1 phase and increase the cell proportion in S phase and G2/M phase U‐2OS/MTX300 in a dose and time‐dependent route through inciting in mice. It additionally activates caspase‐3 and promotes leukemic cell cell apoptosis, cutting down mitochondrial layer potential, releasing of apoptosis, down‐regulates the expression of BCL‐2 and NF‐κB gene, mitochondrial cytochrome c to cytosol, and dephosphorylating of Akt and up‐regulates the expression of Bax gene. These findings suggest (Yin et al., 2012). Similarly, the examination disclosures of Sekeroğlu that quercetin can inhibit leukemia cell proliferation, promote apopto- and Sekeroğlu (2012) demonstrated that treatment with quercetin at sis, and enhance the chemotherapeutic effects of adriamycin through a dose of 50 mg/kg bw/day for 10 days brought in an immense controlling the expression of apoptosis‐related genes (Y. Q. Han, MTX‐induced chromosomal aberrations from the norm in mouse Hong, Su, & Wang, 2014). bone‐marrow cells of mice. It basically cut down the chromosomal Similarly, treatment of human leukemic multidrug resistance aberrations and variation cells (Sekeroğlu & Sekeroğlu, 2012). Querce- K562/adriamycin cells with quercetin promoted cell apoptosis in a tin (50 or 100 mg/kg for 2 days) was neither clastogenic nor dose‐dependent fashion, whereas treatment with a combination of apoptogenic in mice inside and out reduced cisplatin‐induced quercetin and adriamycin resulted in synergistic enhancement of the clastogenesis and apoptosis in the bone marrow cells in dose‐ and apoptotic effect. In addition, treatment of K562/adriamycin cells with time‐dependent manner. These researchers concluded that quercetin quercetin alone or in combination with adriamycin led to (a) loss of has a protective role in the abatement of cisplatin‐induced mitochondrial membrane potential, (b) activation of caspase‐8, ‐9, clastogenesis and apoptosis in the bone marrow cells of mice and that and ‐3, (c) reduction in the antiapoptotic proteins Bcl‐2 and Bcl‐ quercetin can be a good choice to decrease the deleterious effects of extra‐large cisplatin in the bone marrow cells of cancer patients treated with this proapoptotic proteins Bcl‐2‐interacting mediator of cell death, Bcl‐2‐ drug (Attia, 2010). associated death promoter, and Bax in the cells. These findings dem- expression, and (d) improved expression of the In a similar fashion, treatment with quercetin at 10–50 μM doses onstrate that quercetin is important in multidrug resistance and might for 48 achieved clear changes in the scattering of cell cycle phases in be developed into a new reversal agent for cancer chemotherapy (F. Y. the CDDP‐resistant SKOV3/CDDP ovarian cell line. The cyclin D1 Chen, Cao, et al., 2015; X. Chen, Dong, et al., 2015; Q. Chen, Li, et al., expression decreased after quercetin treatment in SKOV3 and 2015). Similar results were obtained by Han and coworkers who U2OSPt cells. (Catanzaro et al., 2015). Similarly, administration of explored the potential antileukemia effects of quercetin along with quercetin (10 μM) inhibited 143B proliferation and up‐regulated the its mechanism of action. These researchers demonstrated that the expression of miR‐217, whereas the target KRAS was down‐regulated combination of adriamycin, an anthracycline antibiotic widely applied both at mRNA and protein levels. Quercetin also regulated cisplatin in the chemotherapy for leukemia, and quercetin shows prolonged sensitivity by modulating the miR‐217‐KRAS axis (X. Zhang, Guo, survival time and less peripheral white blood cells. Quercetin could et al., 2015; J. Y. Zhang, Lin, et al., 2015; X. A. Zhang, Zhang, et al., improve the antileukemic effect of adriamycin through inhibiting the 2015). In human osteosarcoma cell line (MG‐63), quercetin (a) induced proliferation of white blood cells by trapping the cells at the S phase the loss of mitochondrial membrane potential, (b) down‐regulated the and activating caspase‐3 via the expressional regulation of Bcl‐2, expression of antiapoptotic protein, Bcl‐2, (c) up‐regulated the expres- Bax, and NF‐κB (Y. Han et al., 2015). sion of the proapoptotic proteins, Bax, and cytochrome C, and (d) acti- In vitro and in vivo studies on P39 leukemia cells revealed that vated caspase‐3 and caspase‐9 (Liang et al., 2011). It further induced quercetin exhibits marked apoptosis, down‐regulation of Bcl‐2, Bcl‐ apoptosis and significantly reduced mitochondrial membrane poten- xL, and myeloid cell leukemia (Mcl)‐1, up‐regulation of Bax, and mito- tial, caused the release of mitochondrial cytochrome c to the cytosol chondrial translocation, and activating cytochrome c discharge and and activation of caspase‐3, down‐regulated the Bcl‐2, p‐Bad, up‐reg- caspases activation. Additionally, it moreover induced the expression ulated the Bax, and caused dephosphorylating of Akt (Xie et al., 2011). of FasL protein and amplified cell arrest in G1 phase of the cell cycle, with noticeable reduction in cyclin‐dependent kinase 2 (CDK2), CDK6, 2.10 | Blood cancer cyclin D, cyclin E, and cyclin A proteins (Maso et al., 2014). In acute HL‐60 myeloid leukemia (AML) cells, quercetin considerably activated HSP27 enhances the growth of leukemia by shielding cancer cells of caspase‐8, caspase‐9, and caspase‐3, initiated PARP cleavage, and apoptosis. In U937 human leukemia cells, quercetin synergistically caused mitochondrial membrane depolarization. Initiation of PARP inhibits cell propagation and induces apoptosis via lessening the cleavage by quercetin was additionally observed in THP‐1, MV4‐11, Bcl2‐to‐Bax ratio. It considerably suppresses the penetration of tumor and U937 cell lines. Moreover, treatment with quercetin prompted cells and the expression of angiogenesis‐associated proteins HIF1α continued activation of ERK and inhibition of ERK in HL‐60 cells (J. and VEGF. It additionally reduces the protein expression of cyclin Lee, Han, et al., 2015; W. J. Lee, Hsiao, et al., 2015; Y. J. Lee, Lee, & D1 and therefore blocks the cell cycle at G 1 phase. Quercetin consid- Lee, 2015; S. H. Lee, Lee, Min, et al., 2015). erably reduced 2Notch 1 expression and the phosphorylation stages In human K562 chronic myeloid leukemia cells, treatment with of the downstream signaling proteins AKT and mTOR. These results quercetin considerably reduced both the proportion of apoptotic cells suggest that inhibition of HSP27 expression improves the anticancer and caspase‐3 activity. It also altered the cell cycle profile, particularly RAUF 12 after 48 hr of exposure. In addition, it increased the Bcl‐2 protein ET AL. survivin. Interestingly, apoptotic signaling cascades are activated via expression and stopped quercetin‐induced down‐regulation of Mcl‐1 the cleavage of Bid, caspase‐3, and PARP, and by the down‐regulation and Bcl‐xL (Brisdelli et al., 2014). Interestingly, the combination of Bcl‐xL and the up‐regulation of Bax. These results strongly suggest quercetin and menadione (vitamin K3) can improve the outcome of that Sp1 might be a novel molecular target of quercetin in human conventional leukemia therapies mediated by opening of the mito- malignant pleural mesothelioma (Chae et al., 2012). In U87 glioma cells chondrial permeability transition pore (Baran et al., 2014). In EBV‐neg- in a time‐ and dose‐dependent approach, quercetin significantly sup- ative Burkitt's lymphoma cells, quercetin reduced c‐Myc expression pressed the expression of PLD1 at the transcriptional level and addi- and inhibited the PI3K/AKT/mTOR activity. It additionally induced tionally reduced the NFκB‐induced PLD1 expression via inhibition of absolute autophagy flux in Burkitt's lymphoma cells that contributes NFkB transactivation. It also suppressed stimulation of MMP‐2 (Park to c‐Myc reduction in some of these cells (Granato et al., 2016). & Min do, 2011). Q. C. Li, Liang, et al. (2016) and J. Li, Tang, et al. The effects of quercetin on Hedgehog signaling in chronic mye- (2016) have recently studied the effects and interactions of Hsp27 loid leukemia KBM7 cells were recently examined by Li and inhibitor, quercetin, and coworkers. These workers showed that quercetin significantly inhibits cyclohexyloxy]‐benzoic acid on glioblastoma cells and showed that a trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐ KBM7 cell proliferation, induces cell apoptosis, and blocks cell cycle at combination of quercetin and trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐ G1 phase, in dose‐dependent manners. It can also increase p53 and cyclohexyloxy]‐benzoic acid synergistically impedes glioblastoma Caspase‐3 expression (W. Li, Liu, et al., 2014; N. Li, Sun, et al., 2014; growth in vitro and in vivo. Quercetin additionally suppressed COX‐ X. Li, Wang, et al., 2014; W. Li, Zhao, et al., 2014). In a diffuse large 2 expression by inhibiting Hsp27; hence, it acts as both COX‐2 and B‐cell lymphoma cell line, quercetin synergistically improved rituxi- Hsp27 inhibitor (Q. C. Li, Liang, et al., 2016; J. Li, Tang, et al., 2016). mab‐induced growth inhibition and apoptosis. It additionally, exerted Within human GL‐15 glioblastoma cells, quercetin, and other fla- inhibitory activity against STAT3 pathway and down‐regulated the vonoids, reduced the number of feasible cells and the mitochondrial expression of survival genes (W. Li, Liu, et al., 2014; N. Li, Sun, et al., metabolism. Additionally, it damaged mitochondria and rough endo- 2014; X. Li, Wang, et al., 2014; W. Li, Zhao, et al., 2014). In human plasmic reticulum and induced apoptosis. These polyphenols also initi- myeloma cell lines U266, KM3 and RPMI8226, and malignant meso- ated delay cell migration, which is linked to a lessening in filopodia‐like thelioma (MM) derived cells, Ma and colleagues found that quercetin structures on the cell surface, decrease in MMP‐2 expression and inhibits the propagation of MM cells in a dose‐ and time‐dependent action, and an enhancement in intracellular and extracellular expres- manner, accompanied by reduction of IQGAP1 expression at mRNA sion of fibronectin, and intracellular expression of laminin (Santos and protein levels and reduction in ERK1/2 activation. Furthermore, et al., 2015). In multiform glioblastoma U87 cells, diverse concentra- it inhibits the interaction between IQGAP1 and ERK1/2 in RPMI8226 tions of quercetin (50, 100, and 150 μmol/L) induced apoptosis in a cells (Ma et al., 2014). concentration‐dependent fashion by considerably enhancing the Quercetin restores TRAIL‐induced cell death in resistant trans- expression of MDM2 mRNA and active caspase‐3 protein but formed follicular lymphoma B‐cell lines, despite the high Bcl‐2 expres- decreasing the expression of p53 in the cells (H. Wang et al., 2014). sion levels owing to the chromosomal translocation. It rescues In human anaplastic astrocytoma (MOGGCCM) and glioblastoma mul- mitochondrial activity by inducing the proteasomal degradation of tiform (T98G) cell lines, Jakubowicz‐Gil, Langner, Bądziul, Wertel, and Mcl‐1 and by hindering survivin expression at the mRNA level, regard- Rzeski (2013, 2014) have recently investigated the effect of sorafenib less of p53 (Jacquemin et al., 2012). Chang and coworkers have and quercetin on the induction of apoptosis and autophagy. Sorafenib recently investigated the molecular mechanisms by which quercetin and quercetin were effective cell death inducers especially in those exerts its anticancer effects against HL‐60 AML cells. Quercetin sup- cells where the expression of heat shock proteins was blocked. presses cell proliferation in the HL‐60 cell line in vitro and in vivo, Similarly, Pozsgai and coworkers employed techniques such as cell and quercetin‐induced G0/G1‐phase arrest occurs when expressions viability assay, flow cytometry analysis, colony formation assay, and of CDK2/4 are inhibited and the CDK inhibitors, p16 and p21, are western blot analysis to investigate the efficacy of treatment with irra- induced. These researchers concluded that quercetin induces diation, temozolomide, and quercetin, alone, or in combinations, on cytoprotective autophagy in HL‐60 cells, besides promoting apoptosis. two glioblastoma cell lines, DBTRG‐05 and U‐251. A combination of This inhibition of autophagy can be an effective strategy to enhance the agents, including quercetin, greatly reduced cell viability and col- the anticancer activity of quercetin in AML (J.‐L. Chang et al., 2017). ony formation. Quercetin alone, or in combination with irradiation, increased the breakdown of caspase‐3 and PARP‐1, considerably 2.11 | Brain cancer reduced the level of phospho‐Akt, and raised the levels of phospho‐ ERK, phospho‐JNK, phospho‐p38, and phospho‐RAF1. These findings Chae and coworkers evaluated the apoptotic effect of quercetin on suggest that supplementation of standard therapy with quercetin human malignant pleural mesothelioma. Quercetin at 20–80 μM con- enhances the efficiency of treatment of experimental glioblastoma centrations considerably reduced the mesothelioma cell viability and by prompting apoptosis via the cleavage of caspase‐3 and PARP‐1 induced apoptotic cell death in human malignant pleural mesothelioma and by suppressing the activation of Akt pathway (Pozsgai et al., (MSTO‐211H). It additionally enhanced the sub‐G₁ cell population, 2013). In a similar fashion, in C6 glioma cells, quercetin nanoliposomes and was found to interact with Sp1, and considerably inhibited its initiated necrotic cell death and down‐regulated the expression of Bcl‐ expression at the protein and mRNA levels. Quercetin also reduced 2 mRNAs, and enhance the expression of mitochondrial mRNAs the levels of Sp1 regulatory genes, such as cyclin D1, Mcl‐1, and through STAT3‐mediated signaling pathways in C6 glioma cells. These RAUF ET AL. 13 nanoliposomes additionally modulated the mitochondrial and the 2, JNK1/2, p38, p‐p38, Jun proto‐oncogene (c‐JUN), and p‐c‐JUN JAK2/STAT3 signaling pathway (Wang et al., 2013). (Lai et al., 2013). In EGFR‐overexpressing HSC‐3 and TW206 oral On the other hand, quercetin in several cells, including U87‐MG cancer cells, quercetin treatment suppressed cell growth by glioblastoma, U251, and SHG44 glioma cell lines, suppressed cell via- inducing G2 arrest and apoptosis. It additionally suppresses the bility in a dose‐dependent approach. It considerably reduced glioma EGFR/Akt activation with associated initiation of FOXO1 activation. cell migration and enhanced cell senescence and apoptosis. Further- FOXO1 more, treatment with quercetin significantly lowered the protein FasL expression, and subsequent G2 arrest and apoptosis, respectively knockdown reduced quercetin‐induced p21 and intensities of p‐AKT, p‐ERK, MMP‐9, Bcl‐2, and fibronectin. It addi- (C. Y. Huang et al., 2013). tionally suppressed the Ras/MAPK/ERK and PI3K/AKT signaling path- Furthermore, in oral squamous cell carcinoma (SCC), quercetin ways (Pan et al., 2015). Similarly, in U251 and U87 human reduced the cell feasibility and colony‐forming potential in a dose‐ glioblastoma cells, administration of 200 or 400 μmol/L of TMZ alone dependent fashion. It also inhibited the production of SCC‐25 cells efficiently inhibited cell viability, whereas the combination of querce- by means of both G1 phase cell cycle arrest and mitochondria‐medi- tin (30 μmol/L) with TMZ (100 μmol/L) considerably suppressed the ated apoptosis and decreased the abilities of movement and invasion cell viability and enhanced the inhibition rate of TMZ. Additionally, of SCC‐25 cells in a dose‐dependent approach (S. F. Chen et al., the combined effect significantly increased caspase‐3 activity and 2012; S. F. Chen et al., 2013). Quercetin significantly down‐regulated prompted cell apoptosis. Taken all together, treatment with a combi- the aldehyde dehydrogenase 1 activity and productions of Twist, N‐ nation of TMZ and quercetin can competently suppress human glio- cadherin, and vimentin in head and neck cancer‐derived sphere cells blastoma cell survival in vitro (Sang, Li, & Lan, 2014). in a dose‐dependent fashion (W. W. Chang et al., 2013). In DMBA‐ In a similar fashion, quercetin significantly inhibited propagation induced hamster buccal pouch (HBP) carcinogenesis, quercetin has of U373MG cells in a concentration‐dependent approach after 48 chemopreventive and chemotherapeutic special effects on cyto- and 72 hr of incubation. It additionally induced cell death through apo- chrome P450 (CYP)‐mediated ROS production, ROS‐induced cellular ptosis and further (a) enlarged number of cells in the sub‐G1 phase, (b) damage, and activation of the NFκB‐signaling circuit. Administration reduced mitochondrial membrane potential, (c) activated caspase‐3 of quercetin suppressed the growth of DMBA‐induced HBP carcino- and caspase‐7, (d) increased caspase‐3 and 9 activities, and (f) trig- mas by down‐regulation of CYP‐mediated ROS production via gered degradation of PARP. Quercetin also activates JNK, enhances down‐regulation of the expression of CYP1A1 and CYP1B1 and up‐ p53 expression, and initiates autophagy (G. T. Kim, Lee, et al., 2013; regulation of antioxidant defenses. It also mitigates ROS generation H. Kim, Moon, et al., 2013). Moreover, in peripheral T‐cells, quercetin and abolishes NFκB signaling by stopping the phosphorylation and (50 mg/kg) exhibited a small decrease in lymphocytic permeation, a breaking down of IκB, nuclear translocation of NFκB, and marker of good quality diagnosis in gliomas, and a small reduction in transactivation of its target genes related to cell propagation and apo- cell feasibility, in a time‐dependent fashion (Zamin et al., 2014). In ptosis evasion (Priyadarsini & Nagini, 2012). Similarly, in DMBA‐ human glioblastoma multiform T98G cells, quercetin induces apoptosis induced HBP carcinomas, quercetin (a) lessens tumor occurrence and accompanied with activation of caspase 3 and 9 activation, cyto- tumor liability, (b) considerably defers tumor growth, and (c) triggers chrome c release from the mitochondrion, and a drop in the mitochon- cell cycle arrest and apoptosis and blocks invasion and angiogenesis drial membrane potential. Increased expression of caspase 12 and the (Priyadarsini, Vinothini, Murugan, Manikandan, & Nagini, 2011). presence of several granules in the cytoplasm after temozolomide In numerous oral cancer cell lines (SCC‐1483, SCC‐25, and SCC‐ treatment with or without quercetin may propose that apoptosis is ini- QLL1), administration of quercetin at a concentration of 40 μM signif- tiated by endoplasmic reticulum stress (Jakubowicz‐Gil et al., 2013). icantly induced apoptosis and exhibited cleavage of PARP. Furthermore, Caspase‐3 activity assay revealed that induction of apoptosis 2.12 | Head and neck cancer by quercetin was caspase‐3‐dependent (Kang et al., 2010). Similarly, in EGFR‐overexpressing HSC‐3 and FaDu head and neck squamous cell These cancers are more common among men than they are among carcinoma (HNSCC) cells in HNSCC, quercetin at 10 μM suppressed women and are diagnosed more often among people over age 50 than cell migration and invasion. It also inhibits the colony growth of HSC‐ they are among younger people. Treatment for head and neck cancer 3 cells implanted in a Matrigel matrix and suppresses the expression can include surgery, radiation therapy, chemotherapy, targeted ther- and proteolytic activity of MMP‐2 and MMP‐9 in EGFR‐overexpress- apy, or a combination of treatments (American Cancer Society, ing HNSCC. These results indicate that quercetin is an effective anti- 2017a, 2017b). Quercetin in SAS human oral cancer cells has an anti- cancer agent against MMP‐2 and MMP‐9‐mediated metastasis in cancer role by inhibiting the expression and activity of MMP‐2 and EGFR‐overexpressing HNSCC (Chan et al., 2016). Yuan and colleagues MMP‐9 and reducing the protein levels of MMP‐2, ‐7, ‐9, and ‐10, have recently shown that treatment of KB/VCR oral cancer cells with VEGF, and NF‐κB p65. It can also reduce inducible nitric oxide syn- quercetin at 25 to 100 μmol/L effectively inhibits the migration and thase, COX‐2, urokinase‐type plasminogen activator, PI3K, IKBα, invasion of cells and causes cells arrest at the G1 phase and decreases IKB‐α/β, phosphorylated nuclear factor of kappa light polypeptide the amount of cells in the S and G2 phase. These researchers found gene enhancer in B‐cells inhibitor kinase, alpha/beta (p‐IKKα/β), focal that quercetin induces apoptosis, suppresses the expression of Bax, adhesion kinase, son of sevenless homolog‐1, growth factor receptor‐ activates the expression of Caspase‐3 and Bcl‐2, and reverses gene‐ bound protein‐2, mitogen‐activated protein kinase kinase kinase‐3, encoded Pglycoprotein‐mediated MDR in KB/VCR cells by inhibiting mitogen‐activated protein kinase kinase kinase‐7, ERK1/2, p‐ERK1/ the expression of Pglycoprotein (Z. Yuan et al., 2015). RAUF 14 2.13 | Cervical cancer ET AL. from 37% to 83% and increased rate of cell apoptosis from 18.71% ± 2.61% to 70.00% ± 4.05% (W. Zhang & Zhang, 2009). Cervical cancers are some of the principal causes of cancer‐related Finally, recent research by Lin et al. (2017) revealed that luteolin and death among women in developing countries (Ojesina et al., 2014). quercetin considerably prevent ubiquitin E2S ligase expression in cer- Surgery is still the first choice of cervical cancer treatments; however, vical cancer and that high ubiquitin E2S ligase in malignant cancers chemotherapy has been widely suggested to avoid recurrence in post- contributes to cell motility through EMT signaling. operative management of cervical cancers (S. Y. Liu & Zheng, 2013). Due to drug resistance and sever toxicities, there is a need to explore more reliable and less toxic therapeutic approaches to treat cervical 2.14 | Skin cancer cancers. Quercetin proved to be a multipurpose anticancer molecule. Skin cancer is by far the most common type of cancer. It includes mel- In a recent publication, Zhang et al. examined the effect of quercetin anoma, basal and squamous cell, Merkel cell carcinoma, and lymphoma on the expression of heparanase in HeLa and Caski cervical cancer of the skin. Treatment normally includes surgery, radiotherapy, and cells in addition to the molecular mechanism of action. Quercetin less- chemotherapy, in addition to other specialized techniques. On the ened mRNA expression level of HPA, thus causing its reticence in a other hand, ultraviolet (UV) radiation has harmful effects and acts as dose‐ and time‐dependent (W. T. Zhang, Zhang, Zhong, Lü, & Cheng, a tumor maker and promoter. In Hacat cell line, quercetin‐loaded 2013). Quercetin intercalated with calf thymus cell DNA and HeLa cell nanoparticles can significantly protect against UVB irradiation and DNA and suppressed antiapoptotic AKT and Bcl‐2 expression. It has blocks UVB‐induced COX‐2 up‐expression and NF‐kB activation in also been reported for the increase of mitochondrial cytochrome‐c Hacat. In addition, poly(d,l‐lactide‐co‐glycolide)‐d‐α‐tocopheryl poly- level and depolarization of mitochondrial membrane potential with ethylene glycol 1000 succinate (PLGA‐TPGS) nanoparticles could pen- rise of ROS. In the same way, it was found to control the p53 and cas- etrate epidermis and reach dermis. Treatment of mice with quercetin‐ pase‐3 actions. These variations in signaling proteins and externaliza- loaded NPs diminishes UVB irradiation‐related macroscopic and histo- tion of phosphotidyl serine residues are involved with initiation of pathological variations in mice skin. These results demonstrate that apoptosis. Decreased AKT expression proposed in cell production copolymer PLGA‐TPGS could be employed as drug nanocarriers and metastasis potential are accompanied with arrest of the cell cycle against skin damage and disease and provide an external use of at G2/M (Bishayee et al., 2013). A group of researchers showed that in HeLa cells, quercetin PLGA‐TPGS in the treatment of skin diseases (Caddeo et al., 2016; Zhu et al., 2016). appreciably retards the growth and induces apoptosis in vitro in a Quercetin is a well‐known inhibitor of PI3K and MAP kinase sig- time‐ and dose‐dependent fashion. It causes cell cycle arrest at G0/ naling. In UV‐B‐irradiated B16F10 melanoma cells, treatment with G1 phase and further down‐regulates the expression of the PI3K quercetin caused a decrease in cell viability and amplified apoptosis and p‐Akt. It could additionally down‐regulate the expression of bcl‐ in a dose‐dependent fashion. The proapoptotic effects of quercetin 2 and up‐regulate Bax. These findings suggest that quercetin induces in UVB‐irradiated B16F10 cells are mediated through (a) promotion apoptosis in HeLa cells through PI3k/Akt pathways (Xiang et al., of intracellular ROS formation, (b) calcium homeostasis disparity, (c) 2014). In a similar fashion, Wang and coworkers employed MTT, flow variation of antioxidant defense response, and (d) depolarization of cytometry, and MDC staining to evaluate proliferation, apoptosis, and mitochondrial membrane potential (ΔΨM). Additionally, enhancement autophagy, respectively, after treatment with quercetin in HeLa cells. of UVB‐induced cell death by quercetin was revealed by breaking In addition, they used western blot assay to detect LC3‐I/II, Beclin 1, down of chromosomal DNA, caspase activation, PARP cleavage, and active caspase‐3, and S6K1 phosphorylation. Results revealed that a rise in sub‐G1 cells. Furthermore, quercetin significantly reduces quercetin can inhibit HeLa cell production and initiate protective MEK–ERK signaling, effects PI3K/Akt pathway, and improves the autophagy at low concentrations (P. Wang, Henning, et al., 2016; Y. UVB‐induced NF‐κB nuclear translocation. Similarly, a combined treat- Wang, Zhang, et al., 2016). In human cervical carcinoma HeLa cells, ment with UVB and quercetin decreased the ratio of Bcl‐2 to that of quercetin caused introduction of apoptosis and remained efficient Bax and up‐regulated the expression of Bim and apoptosis‐inducing for extended period of time (48 hr), decreased Hsp27 and Hsp72 factor. These results suggest the possibility of using quercetin in com- expression, and raised caspases actions (Bądziul, Jakubowicz‐Gil, bination with UVB as a promising treatment alternative for melanoma Paduch, Głowniak, & Gawron, 2014; Luo et al., 2016). in the future (Rafiq et al., 2015). In human cervical cancer (HeLa) cells, quercetin suppressed cell In a skin carcinogenesis mouse model, skin tumor was induced by viability in a dose‐dependent fashion by initiation of G2/M phase cell DMBA and croton oil in Swiss albino mouse. Oral administration of cycle arrest and mitochondrial apoptosis via a p53‐dependent mecha- quercetin, at a concentration of 200 and 400 mg/kg body weight daily nism (Vidya Priyadarsini et al., 2010). Additionally, in transplanted car- for 16 weeks, reduced the tumor size and the number of papillomas. In cinoma in BALB/C nude mice, quercetin at different concentrations addition, quercetin significantly reduced the serum levels of glutamate (6.25, 12.5, 25, and 50 μmol/L) for 24 hr (a) increased the suppression oxalate transaminase, glutamate pyruvate transaminase, and alkaline rate of the cells, (b) induced apoptosis, (c) considerably lessened mito- phosphatase and bilirubin and considerably elevated the levels of glu- chondrial membrane potential, (d) effectively enhanced the [Ca2+]i, tathione, superoxide dismutase, and catalase. It additionally prevented and (e) activated the caspase‐3 in a dose‐dependent manner (L. Q. lipid peroxides production and reduced DNA damage as compared Huang, Zhang, Yang, & Tao, 2009). Furthermore, in Hela cells, querce- with DMBA and croton oil‐treated mice (Ali & Dixit, 2015). On the tin at concentrations of 20 to 80 μM increased the cell inhibition rate other hand, in a DMBA‐tetradecanoyl phorbol‐13‐acetate two stage RAUF ET AL. 15 mouse skin carcinogenesis protocol, the quercetin diet (0.02% wt/wt) synergistically to overcome drug resistance. In their study, two known for 20 weeks extraordinarily deferred the occurrence of skin tumor by anticancer phytochemicals, quercetin and thymoquinone, were com- 2 weeks and reduced tumor growth by 35%. Additionally, quercetin bined with two platinum drugs, cisplatin and oxaliplatin, which are supplementation substantially inhibited skin hyperplasia in Tg mice commonly used to treat different types of cancer, including ovarian and suppressed (a) IGF‐1 induced phosphorylation of the IGF‐1 recep- cancer. This combination was tried against two human epithelial ovar- tor, (b) insulin receptor substrate‐1, (c) Akt and S6K, and (d) IGF‐1 ian cancer cell lines, A2780 and its cisplatin‐resistant form A2780. stimulated cell production, in a dose‐dependent approach. These Results revealed that the greatest synergism is achieved when the results suggest that quercetin exerts its anticancer activity through phytochemical is added first followed by platinum drug 2 hr later, the inhibition of IGF‐1 signaling (Jung, Bu, Tak, Park, & Kim, 2013). and the least synergism is observed when the two compounds were administered as a bolus. It was then suggested that addition of the 2.15 | phytochemical 2 hr before platinum drug may sensitize cancer cells Eye cancer to platinum action, thus offering a means to overcome drug resistance In human retinal pigment epithelial cells, quercetin, and other flavonoids, reduced, in a dose‐dependent fashion, the retinal pigment epithelial cell propagation, migration, and secretion of VEGF. It additionally inhibited the secretion of VEGF prompted by CoCl2‐ induced hypoxia and substantially decreased cell viability by triggering cellular necrosis (R. Chen et al., 2014). (Nessa, Beale, Chan, Yu, & Huq, 2011). Similarly, researchers encapsulated quercetin into biodegradable monomethoxy poly(ethylene glycol)‐poly (ε‐caprolactone) micelles for treating ovarian cancer, in an effort to increase its solubility in water. This nano‐formulation of quercetin dose‐dependently prevented the growth of A2780S ovarian cancer cells. In addition, treatment with quercetin induced apoptosis of A2780S cells and stimulated caspase‐3 and caspase‐9, down‐regu- 2.16 | Thyroid cancer Radioactive iodine (best known as lated MCL‐1 and Bcl‐2, and up‐regulated Bax and changed mitochon131 I) is commonly employed in treating patients with thyroid diseases, including thyroid cancer and Graves' disease. Side effects of this treatment include DNA damage and chromosomal breakdowns, which could lead to cell death (Robbins & Schlumberger, 2005). Moreover, 131 I treatment is linked with increased genetic damage, and the occurrence of secondary malignancies and leukemia might increase with higher doses of radioiodine (Chow, 2005). Accordingly, there is a pressing need for protection of normal cells, which may mitigate side effects induced by 131I. In human papillary thyroid cancer cells, quercetin has been shown to significantly lower cell proliferation and improves the rate of apoptosis by caspase activation. It, additionally, induces cell apoptosis by down‐regulation of Hsp90 expression. The decrease of chymotrypsin‐like proteasome activity suppresses growth and causes cell death in thyroid cancer cells (Mutlu Altundağ et al., 2016). In human medullary and papillary thyroid cancer cells, Quagliariello et al. showed that quercetin delivered from hydrogel displays a time‐ and CD44‐dependent interaction with both cell lines with significant anti‐inflammatory effects. On the other hand, a combination of quercetin and SNS‐314 results in a synergistic cytotoxic effect on medullary TT and papillary BCPAP cell lines with a significant decrease of the IC50 value (Quagliariello et al., 2016). Similarly, treatment of thyroid papillary cancer cell lines with different concentrations of quercetin (between 10 and 75 μM) for 24 hr induces apoptosis by inhibiting HSP production on various cancer cell lines (Mutlu Altundag et al., 2014). drial transmembrane potential. These events suggest that quercetin may induce apoptosis of A2780S cells via the mitochondrial apoptotic pathway (Gao et al., 2012). Maciejczyk and Surowiak explored the effect of low doses of quercetin on the sensitivity of human ovarian cancer cell lines, SKOV‐3, EFO27, OVCAR‐3, and A278OP, and the effect on the sensitivity of these cell lines to cisplatin and paclitaxel. These researchers demonstrated that low doses of quercetin increase sensitivity of ovarian cancer cells to cisplatin and paclitaxel (Maciejczyk & Surowiak, 2013). In cisplatin‐sensitive and cisplatin‐resistant A2780s and A2780cp human ovarian cancer cell lines, the mixture liposomal‐quercetin considerably suppressed tumor progression in both cell lines compared with free liposomes or quercetin. Furthermore, it induced apoptosis, decreased microvessel density, and inhibited proliferation of tumors in both cell lines (Long et al., 2013). Additionally, quercetin could sensitize human ovarian cancer cells to TRAIL and induced expression of DR5. Stimulation of DR5 was mediated via activation of JNK and up‐regulation of a transcription factor CHOP. Up‐regulation of DR5 was also mediated by production of ROS. These results suggest that quercetin enhancement of TRAIL‐mediated inhibition of tumor growth of human SKOV‐3 xenograft is associated with apoptosis and activation of caspase‐3, CHOP, and DR5 (Yi et al., 2014). In human ovarian cancer C13* and SKOV3 cells, quercetin at concentrations of 40–100 μM displayed proapoptotic effect. In addition, it suppressed ROS‐induced injury, reduced intracellular ROS level, and improved the expression of endogenous antioxidant enzymes. 2.17 | Ovarian cancer These results suggest an ROS‐mediated mechanism of reducing antineoplastic drugs. Furthermore, quercetin triggered a considerable Ovarian cancer, one of the most common female malignancies, reduction of therapeutic efficiency of cisplatin and ROS‐induced dam- accounts for the leading death rate among the gynecologic cancers. age in xenograft tumor tissue (W. Li, Liu, et al., 2014; N. Li, Sun, et al., Risk factors include age, null parity, early menarche, late menopause, 2014; X. Li, Wang, et al., 2014; W. Li, Zhao, et al., 2014). Similarly, and family history, whereas pregnancy and breastfeeding decrease quercetin repressed the proliferation of SKOV‐3 cells in a time‐ and this risk (Gao et al., 2012). dose‐dependent approach, prompted cell apoptosis, and initiated In the quest to develop drugs for cancer chemotherapy, Nessa ovarian cancer SKOV‐3 cell cycle arrest in the G0/G1 phase and a sub- and colleagues examined the use of combination of drugs acting stantial reduction in the percentage of cells at the G2/M phase RAUF 16 ET AL. (Arzuman, Beale, Yu, & Huq, 2015; Ren, Deng, Ai, Yuan, & Song, investigated the anticancer activity of a 1:1 combination of quercetin 2015). Additionally, treatment of SKOV‐3 and OVCAR‐8 ovarian can- and hyperoside on 786‐O renal cancer cells. The combination cer cells with quercetin induced apoptosis, activated caspase‐3 and decreased the production of ROS by up to 2.25‐fold and increased increased sensitivity to cisplatin, and reduced expression and activa- the antioxidant ability by up to threefold in these cells. In addition, it tion of EGFR. induced caspase‐3 cleavage (twofold), increased PARP cleavage, and In addition, quercetin deactivated MAPK–ERK pathway; induced reduced the expression of specificity protein Sp1, Sp3, and Sp4 mRNA down‐regulation of cyclin D1, DNA‐PK, phospho‐histone H3, and (W. Li, Liu, et al., 2014; N. Li, Sun, et al., 2014; X. Li, Wang, et al., 2014; up‐regulation of p21; and arrested cell cycle development (Y. Wang, W. Li, Zhao, et al., 2014). Han, et al., 2015; P. Wang, Henning, et al., 2015; P. Wang, Phan, et al., 2015; J. Wang, Zhang, et al., 2015). Similarly, quercetin significantly improved the expression levels of cleaved caspase‐3 and 2.19 prompted overexpression of miR‐145 in SKOV‐3 and A2780 ovarian In MM SPC212 and SPC111 cell lines, quercetin substantially sup- cancer cells (Zhou, Gong, Ding, & Chen, 2015). Furthermore, in ovarian pressed the propagation of cancer, modified the cell cycle distribution, cancer, pretreatment with quercetin considerably increased cisplatin and increased the level of caspase 9 and caspase 3 in a concentration cytotoxicity and activated the three branches of endoplasmic reticu- and time‐dependent fashion (Demiroglu‐Zergeroglu, Basara‐Cigerim, lum stress. It additionally suppressed STAT3 phosphorylation, leading Kilic, & Yanikkaya‐Demirel, 2010). Quercetin and quercetin in combi- to down‐regulation of the BCL‐2 gene downstream of STAT3, and nation with cisplatin also moderated gene expression of cyclins, improved the antitumor effect of cisplatin in a xenograft mouse model cyclin‐dependent kinases, and cyclin‐dependent kinases inhibitors of ovarian cancer (Arzuman, Beale, Chan, Yu, & Huq, 2014; F. Q. Yang, and up‐regulated genes involved in JNK, p38, and MAPK/ERK path- Liu, Li, et al., 2015; Z. Yang, Liu, Liao, et al., 2015; F. Yang, Song, et al., ways. Moreover, quercetin + cisplatin increased phosphorylations of | Mesothelioma cancer 2015). Finally, a review pertaining to quercetin and ovarian cancer has p38 and JNK and decreased and that of ERK (Demiroglu‐Zergeroglu been recently published (Parvaresh et al., 2016). et al., 2016). In MM MSTO‐211H and H2452 cells, Lee and coworkers found 2.18 | Kidney cancer that quercetin treatment suppresses cell growth by up‐regulating Nrf2 at both the mRNA and protein levels. Reduction of Nrf2 expres- Kidney cancer, also known as renal cancer, is a type of cancer that sion with siRNA improved cytotoxicity, as demonstrated by (a) an starts in the cells in the kidney. Factors that increase the risk of kidney increase in the level of proapoptotic Bax, (b) a decline in the extent cancer include smoking, which can double the risk of the disease, reg- of antiapoptotic Bcl‐2 with improved cleavage of caspase‐3 and PARP ular use of nonsteroidal anti‐inflammatory drugs such as ibuprofen proteins, and (c) the appearance of a sub‐G0/G1 peak in the flow and naproxen, obesity, faulty genes, a family history of kidney cancer, cytometric assay. These findings highlight the importance of Nrf2 in having kidney disease that needs dialysis, being infected with hepatitis cytoprotection, survival, and drug resistance, in addition to the poten- C, and previous treatment for testicular cancer or cervical cancer tial significance of targeting Nrf2 as a promising strategy for overcom- (Lipworth, Tarone, & McLaughlin, 2006). ing resistance to chemotherapeutics in MM (J. Lee, Han, et al., 2015; Protective effect of quercetin against cisplatin nephrotoxicity in a rat tumor model was evaluated by a number of scientists. Co‐treat- W. J. Lee, Hsiao, et al., 2015; Y. J. Lee, Lee, & Lee, 2015; S. H. Lee, Lee, Min, et al., 2015). ment with quercetin can partially prevent all renal effects of cisplatin without affecting its antitumor activity (Sanchez‐Gonzalez, Lopez‐ Hernandez, Perez‐Barriocanal, Morales, & Lopez‐Novoa, 2011). On 3 | CO NC LUSIO NS the other hand, the antitumor effect of quercetin, combined with antisense oligo gene therapy (inhibiting Snail gene), was recently investi- Diet in combination with chemotherapeutics agents has been gaining gated by Meng et al. (2015). Results revealed that in a Caki‐2 clear popularity in the fight against diseases such as cardiovascular disor- cell renal cell carcinoma (ccRCC) cell line, each of the investigated ders, cancer insurgence, and immune dysfunction. In addition, utiliza- therapeutic agents considerably suppressed cell proliferation and tion of conventional therapies such as natural products, particularly migration and triggered cell cycle arrest and apoptosis. However, the in treating cancer, has attracted the attention of the scientific and combination of both agents provided even strong inhibitory effects medical communities due to their lesser side effects and cost. Querce- toward these cancer cells. This study clearly highlights the use of a tin, a flavonoid antioxidant found in plant foods, such as leafy greens, combination of natural products and gene therapy for the treatment tomatoes, berries, broccoli, onions, and apples, is considered as one of of renal cancer (Meng et al., 2015). Heeba and Mahmoud have probed the most abundant antioxidants in the human diet and plays an impor- the effects of different doses of quercetin on Dox‐induced nephrotox- tant role in fighting free radical damage, the effects of aging, and icity in rats. Results showed that oral administration of quercetin to inflammation. Its wide accessibility, efficacy, and a broad range of adult male Albino rats for 14 days preserved renal function by reduc- activity, and low toxicity as compared with other examined com- ing blood urea nitrogen, serum creatinine, renal malondialdehyde, pounds, make it an attractive chemical in the fight against diseases nitric oxide, reduced glutathione, catalase activity, and renal expres- including cancer. It has been recognized and employed as an alterna- sions of TNF‐a, IL‐1B, inducible nitric oxide synthase, and caspase‐3 tive drug in treating different cancers alone or in combination with (Heeba & Mahmoud, 2016). In a similar fashion, Li and colleagues other chemotherapeutic drugs. Certainly, a variety of evidences have RAUF ET AL. 17 been presented in its favor in combatting cancer; however, some reports demand that further scientific research is needed. In this review, we have shown that quercetin provides a wide range of preventive and therapeutic options against different types of cancer, along with a description of the various mechanisms by which this compound exerts its action. In summary, this review reveals that quercetin can be an important complementary medicine for the prevention and treatment of different types of cancers, owing to its natural origin, safety, and low cost relative to synthetic cancer drugs. However, further studies are needed on this natural compound. Furthermore, because most of the findings cited in the current review are based on in vitro and in vivo studies, which do not necessarily represent the effect of quercetin in human, more investigations that involve different pharmacokinetic parameter are recommended in the future before this substance hits the market as a prescribed drug. Moreover, development of standardized extract or dosage could also be pursued in clinical trials. CONF LICT S OF INTE R ES T Authors declare no conflict of interest. ORCID Mohammad S. Mubarak http://orcid.org/0000-0002-9782-0835 RE FE R ENC E S Abarikwu, S. O., Pant, A. B., & Farombi, E. O. (2012). Dietary antioxidant, quercetin, protects sertoli‐germ cell coculture from atrazine‐induced oxidative damage. Journal of Biochemical and Molecular Toxicology, 26, 477–485. Ali, H., & Dixit, S. (2015). Quercetin attenuates the development of 7,12‐ dimethyl benz (a) anthracene (DMBA) and croton oil‐induced skin cancer in mice. Journal of Biomedical Research, 29, 139–144. Amado, N. G., Predes, D., Fonseca, B. F., Cerqueira, D. M., Reis, A. H., Dudenhoeffer, A. C., … Abreu, J. G. (2014). Isoquercitrin suppresses colon cancer cell growth in vitro by targeting the Wnt/β‐catenin signaling pathway. The Journal of Biological Chemistry, 289, 35456–35467. American Cancer Society. (2017a). Cancer Facts and Figures 2017 Exit Disclaimer. Atlanta, GA. American Cancer Society (2017b). Retrieved March 29, 2017. Angst, E., Park, J. L., Moro, A., Lu, Q. Y., Lu, X., Li, G., … Hines, O. J. (2013). The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo. Pancreas, 42, 223–229. Appari, M., Babu, K. R., Kaczorowski, A., Gross, W., & Herr, I. (2014). Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR‐let‐7 induction and K‐ras inhibition. International Journal of Oncology, 45, 1391–1400. Arzuman, L., Beale, P., Chan, C., Yu, J. Q., & Huq, F. (2014). Synergism from combinations of tris (benzimidazole) monochloroplatinum (II) chloride with capsaicin, quercetin, curcumin and cisplatin in human ovarian cancer cell lines. Anticancer Research, 34, 5453–5464. Arzuman, L., Beale, P., Yu, J. Q., & Huq, F. (2015). Monofunctional platinum‐containing pyridine‐based ligand acts synergistically in combination with the phytochemicals curcumin and quercetin in human ovarian tumor models. Anticancer Research, 35, 2783–2794. Atashpour, S., Fouladdel, S., Movahhed, T. K., Barzegar, E., Ghahremani, M. H., Ostad, S. N., & Azizi, E. (2015). Quercetin induces cell cycle arrest and apoptosis in CD133(+) cancer stem cells of human colorectal HT29 cancer cell line and enhances anticancer effects of doxorubicin. Iranian Journal of Basic Medical Sciences, 18, 635–643. Attia, S. M. (2010). The impact of quercetin on cisplatin‐induced clastogenesis and apoptosis in murine marrow cells. Mutagenesis, 25, 281–288. Bądziul, D., Jakubowicz‐Gil, J., Paduch, R., Głowniak, K., & Gawron, A. (2014). Combined treatment with quercetin and imperatorin as a potent strategy for killing HeLa and Hep‐2 cells. Molecular and Cellular Biochemistry, 392, 213–227. Balakrishnan, S., Bhat, F. A., Raja Singh, P., Mukherjee, S., Elumalai, P., Das, S., … Arunakaran, J. (2016). Gold nanoparticle‐conjugated quercetin inhibits epithelial‐mesenchymal transition, angiogenesis, and invasiveness via EGFR/VEGFR‐2‐mediated pathway in breast cancer. Cell Proliferation, 49, 678–697. Balakrishnan, S., Mukherjee, S., Das, S., Bhat, F. A., Raja Singh, P., Patra, C. R., & Arunakaran, J. (2017). Gold nanoparticles–conjugated quercetin induces apoptosis via inhibition of EGFR/PI3K/Akt–mediated pathway in breast cancer cell lines (MCF‐7 and MDA‐MB‐231). Cell Biochemistry and Function, 35, 217–231. Baran, I., Ionescu, D. A., Filippi, A., Mocanu, M. M., Iftime, A., Babes, R., … Ganea, C. (2014). Novel insights into the antiproliferative effects and synergism of quercetin and menadione in human leukemia Jurkat T cells. Leukemia Research, 38, 836–849. Baruah, M. M., Khandwekar, A. P., & Sharma, N. (2016). Quercetin modulates Wnt signaling components in prostate cancer cell line by inhibiting cell viability, migration, and metastases. Tumor Biology, 37, 14025–14034. Benavente‐Garcia, O., & Castillo, J. (2008). Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti‐inflammatory activity. Journal of Agricultural and Food Chemistry, 56, 6185–6205. Berndt, K., Campanile, C., Muff, R., Strehler, E., Born, W., & Fuchs, B. (2013). Evaluation of quercetin as a potential drug in osteosarcoma treatment. Anticancer Research, 33, 1297–1306. Bishayee, K., Ghosh, S., Mukherjee, A., Sadhukhan, R., Mondal, J., & Khuda‐ Bukhsh, A. R. (2013). Quercetin induces cytochrome‐c release and ROS accumulation to promote apoptosis and arrest the cell cycle in G2/M, in cervical carcinoma: Signal cascade and drug‐DNA interaction. Cell Proliferation, 46, 153–163. Bishayee, K., Khuda‐Bukhsh, A. R., & Huh, S. O. (2015). PLGA‐Loaded gold‐ nanoparticles precipitated with quercetin downregulate HDAC‐Akt activities controlling proliferation and activate p53‐ROS crosstalk to induce apoptosis in hepatocarcinoma cells. Molecules and Cells, 38, 518–527. Borska, S., Chmielewska, M., Wysocka, T., Drag‐Zalesinska, M., Zabel, M., & Dziegiel, P. (2012). In vitro effect of quercetin on human gastric carcinoma: Targeting cancer cells death and MDR. Food and Chemical Toxicology, 50, 3375–3383. Brisdelli, F., Bennato, F., Bozzi, A., Cinque, B., Mancini, F., & Iorio, R. (2014). ELF‐MF attenuates quercetin‐induced apoptosis in K562 cells through modulating the expression of Bcl‐2 family proteins. Molecular and Cellular Biochemistry, 397, 33–43. Brito, A. F., Ribeiro, M., Abrantes, A. M., Pires, A. S., Teixo, R. J., Tralhão, J. G., & Botelho, M. F. (2015). Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Current Medicinal Chemistry, 22, 3025–3039. Caddeo, C., Nacher, A., Vassallo, A., Armentano, M. F., Pons, R., Fernàndez‐ Busquets, X., … Manconi, M. (2016). Effect of quercetin and resveratrol co‐incorporated in liposomes against inflammatory/oxidative response associated with skin cancer. International Journal of Pharmacology, 513, 153–163. Cao, C., Sun, L., Mo, W., Sun, L., Luo, J., Yang, Z., & Ran, Y. (2015). Quercetin‐mediates β‐catenin in pancreatic cancer stem‐like cells. Pancreas, 44, 1334–1339. Catanzaro, D., Ragazzi, E., Vianello, C., Caparrotta, L., & Montopoli, M. (2015). Effect of quercetin on cell cycle and cyclin expression in ovarian carcinoma and osteosarcoma cell lines. Natural Product Communications, 10, 1365–1368. 18 Chae, J. I., Cho, J. H., Lee, K. A., Choi, N. J., Seo, K. S., Kim, S. B., … Shim, J. H. (2012). Role of transcription factor Sp1 in the quercetin‐mediated inhibitory effect on human malignant pleural mesothelioma. International Journal of Molecular Medicine, 30, 835–841. Chan, C. Y., Lien, C. H., Lee, M. F., & Huang, C. Y. (2016). Quercetin suppresses cellular migration and invasion in human head and neck squamous cell carcinoma (HNSCC). Biomedicine (Taipei), 6, 15. RAUF ET AL. activity in colon cancer cells and repress oncogenic microRNA‐27a. Nutrition and Cancer, 65, 494–504. Demiroglu‐Zergeroglu, A., Basara‐Cigerim, B., Kilic, E., & Yanikkaya‐ Demirel, G. (2010). The investigation of effects of quercetin and its combination with cisplatin on malignant mesothelioma cells in vitro. Journal of Biomedicine and Biotechnology, 2010, 851589. Chang, J.‐L., Chow, J.‐M., Chang, J.‐H., Wen, Y. C., Lin, Y. W., Yang, S. F., … Chien, M. H. (2017). Quercetin simultaneously induces G0/G1‐phase arrest and caspase‐mediated crosstalk between apoptosis and autophagy in human leukemia HL‐60 cells. Environmental Toxicology, 32, 1857–1868. Demiroglu‐Zergeroglu, A., Ergene, E., Ayvali, N., Kuete, V., & Sivas, H. (2016). Quercetin and cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells. BMC Complementary and Alternative Medicine, 16, 281. Chang, W. W., Hu, F. W., Yu, C. C., Wang, H. H., Feng, H. P., Lan, C., … Chang, Y. C. (2013). Quercetin in elimination of tumor initiating stem‐ like and mesenchymal transformation property in head and neck cancer. Head & Neck, 35, 413–419. Dhumale, S. S., Waghela, B. N., & Pathak, C. (2015). Quercetin protects necrotic insult and promotes apoptosis by attenuating the expression of RAGE and its ligand HMGB1 in human breast adenocarcinoma cells. IUBMB Life, 67, 361–373. Chen, F. Y., Cao, L. F., Wan, H. X., Zhang, M. Y., Cai, J. Y., Shen, L. J., … Zhong, H. (2015). Quercetin enhances adriamycin cytotoxicity through induction of apoptosis and regulation of mitogen‐activated protein kinase/extracellular signal‐regulated kinase/c‐Jun N‐terminal kinase signaling in multidrug‐resistant leukemia K562 cells. Molecular Medicine Reports, 11, 341–348. Di Lorenzo, G., Pagliuca, M., Perillo, T., Zarrella, A., Verde, A., De Placido, S., & Buonerba, C. (2016). Complete response and fatigue improvement with the combined use of cyclophosphamide and quercetin in a patient with metastatic bladder cancer: A case report. Medicine (Baltimore), 95, e2598. Chen, Q., Li, P., Li, P., Xu, Y., Li, Y., & Tang, B. (2015). Isoquercitrin inhibits the progression of pancreatic cancer in vivo and in vitro by regulating opioid receptors and the mitogen‐activated protein kinase signalling pathway. Oncology Reports, 33, 840–848. Chen, R., Hollborn, M., Grosche, A., Reichenbach, A., Wiedemann, P., Bringmann, A., & Kohen, L. (2014). Effects of the vegetable polyphenols epigallocatechin‐3‐gallate, luteolin, apigenin, myricetin, quercetin, and cyanidin in primary cultures of human retinal pigment epithelial cells. Molecular Vision, 20, 242–258. Chen, S. F., Nieh, S., Jao, S.‐W., Liu, C.‐L., Wu, C.‐H., Chang, Y.‐C., … Lin, Y.‐S. (2012). Quercetin suppresses drug‐resistant spheres via the p38 MAPK– Hsp27 apoptotic pathway in oral cancer cells. PLoS One, 7, e49275. Chen, S. F., Nien, S., Wu, C. H., Liu, C. L., Chang, Y. C., & Lin, Y. S. (2013). Reappraisal of the anticancer efficacy of quercetin in oral cancer cells. Journal of the Chinese Medical Association, 76(3), 146–152. Chen, W., Padilla, M. T., Xu, X., Desai, D., Krzeminski, J., Amin, S., & Lin, Y. (2016). Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. Molecular Carcinogenesis, 55, 1858–1866. Chen, W., Wang, X., Zhuang, J., Zhang, L., & Lin, Y. (2007). Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL‐induced cytotoxicity by quercetin in non‐small cell lung cancer cells. Carcinogenesis, 28(10), 2114–2121. Chen, X., Dong, X. S., Gao, H. Y., Jiang, Y. F., Jin, Y. L., Chang, Y. Y., … Wang, J. H. (2015). Suppression of HSP27 increases the anti‐tumor effects of quercetin in human leukemia U937 cells. Molecular Medicine Reports, 13, 689–696. Cho, S. Y., Kim, M. K., Park, K. S., Choo, H., & Chong, Y. (2013). Quercetin‐ POC conjugates: Differential stability and bioactivity profiles between breast cancer (MCF‐7) and colorectal carcinoma (HCT116) cell lines. Bioorganic and Medicinal Chemistry, 21, 1671–1679. Gao, X., Wang, B., Wei, X., Men, K., Zheng, F., Zhou, Y., … Wei, Y. (2012). Anticancer effect and mechanism of polymer micelle‐encapsulated quercetin on ovarian cancer. Nanoscale, 4, 7021–7030. Granato, M., Rizzello, C., Romeo, M. A., Yadav, S., Santarelli, R., D'Orazi, G., … Cirone, M. (2016). Concomitant reduction of c‐Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt's lymphoma. The International Journal of Biochemistry and Cell Biology, 79, 393–400. Guan, X., Gao, M., Xu, H., Zhang, C., Liu, H., Lv, L., … Tian, Y. (2016). Quercetin‐loaded poly(lactic‐co‐glycolic acid)‐d‐α‐tocopheryl polyethylene glycol 1000 succinate nanoparticles for the targeted treatment of liver cancer. Drug Delivery, 23, 3307–3318. Hamidullah, Kumar, R., Saini, K. S., Kumar, A., Kumar, S., Ramakrishna, E., … Chattopadhyay, N. (2015). Quercetin‐6‐C‐β‐D‐glucopyranoside, natural analog of quercetin exhibits anti‐prostate cancer activity by inhibiting Akt‐mTOR pathway via aryl hydrocarbon receptor. Biochimie, 119, 68–79. Han, M., Song, Y., & Zhang, X. (2016). Quercetin suppresses the migration and invasion in human colon cancer caco‐2 cells through regulating toll‐like receptor 4/nuclear factor‐kappa B pathway. Pharmacognosy Magazine, 12, S237–S244. Han, Y., Yu, H., Wang, J., Ren, Y., Su, X., & Shi, Y. (2015). Quercetin alleviates myocyte toxic and sensitizes anti‐leukemic effect of adriamycin. Hematology, 20, 276–283. Han, Y. Q., Hong, Y., Su, X. L., & Wang, J. R. (2014). Quercetin enhances the anti‐leukemic effect of Adriamycin. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 22, 1555–1560. Harris, D. M., Li, L., Chen, M., Lagunero, F. T., Go, V. L. W., & Boros, L. G. (2012). Diverse mechanisms of growth inhibition by luteolin, resveratrol, and quercetin in MIA PaCa‐2 cells: A comparative glucose tracer study with the fatty acid synthase inhibitor C75. Metabolomics, 8, 201–210. Chow, S. M. (2005). Side effects of high‐dose radioactive iodine for ablation or treatment of differentiated thyroid carcinoma. Hong Kong Journal of Radiology, 8, 127–135. Heeba, G. H., & Mahmoud, M. E. (2016). Dual effects of quercetin in doxorubicin‐induced nephrotoxicity in rats and its modulation of the cytotoxic activity of doxorubicin on human carcinoma cells. Environmental Toxicology, 31, 624–636. Chuang, C. H., Yeh, C. L., Yeh, S. L., Lin, E. S., Wang, L. Y., & Wang, Y. H. (2016). Quercetin metabolites inhibit MMP‐2 expression in A549 lung cancer cells by PPAR‐γ associated mechanisms. Journal of Nutritional Biochemistry, 33, 45–53. Huang, C. Y., Chan, C. Y., Chou, I. T., Lien, C. H., Hung, H. C., & Lee, M. F. (2013). Quercetin induces growth arrest through activation of FOXO1 transcription factor in EGFR‐overexpressing oral cancer cells. The Journal of Nutritional Biochemestry, 24, 1596–1603. de Martel, C., Ferlay, J., Franceschi, S., Vignat, J., Bray, F., Forman, D., & Plummer, M. (2012). Global burden of cancers attributable to infections in 2008: A review and synthetic analysis. Lancet Oncology, 13, 607–615. Huang, L. Q., Zhang, W., Yang, Y., & Tao, L. (2009). Effects and its mechanism of quercetin on cervical cancer HeLa cells. Zhonghua Fu Chan Ke Za Zhi, 44, 436–439. Del Follo‐Martinez, A., Banerjee, N., Li, X., Safe, S., & Mertens‐Talcott, S. (2013). Resveratrol and quercetin in combination have anticancer Iacopetta, D., Grande, F., Caruso, A., Mordocco, R. A., Plutino, M. R., Scrivano, L., … Sinicropi, M. S. (2017). New insights for the use of RAUF ET AL. 19 quercetin analogs in cancer treatment. Future Medicinal Chemistry, 9(17), 2011–2028. microRNA expression in lung cancer tissues. Cancer Epidemiology, Biomarkers & Prevention, 21, 2176–2184. Jacquemin, G., Granci, V., Gallouet, A. S., Lalaoui, N., Morle, A., Iessi, E., … Micheau, O. (2012). Quercetin‐mediated Mcl‐1 and survivin downregulation restores TRAIL‐induced apoptosis in non‐Hodgkin's lymphoma B cells. Haematologica, 97, 38–46. Lee, H. H., Lee, S., Shin, Y. S., Cho, M., Kang, H., & Cho, H. (2016). Anti‐cancer effect of quercetin in xenograft models with EBV‐associated human gastric carcinoma. Molecules, 21, 1286. Jakubowicz‐Gil, J., Langner, E., Bądziul, D., Wertel, I., & Rzeski, W. (2013). Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment. Toxicology and Applied Pharmacology, 273, 580–589. Jakubowicz‐Gil, J., Langner, E., Bądziul, D., Wertel, I., & Rzeski, W. (2014). Quercetin and sorafenib as a novel and effective couple in programmed cell death induction in human gliomas. Neurotoxicity Research, 26, 64–77. Jung, M., Bu, S. Y., Tak, K. H., Park, J. E., & Kim, E. (2013). Anticarcinogenic effect of quercetin by inhibition of insulin‐like growth factor (IGF)‐1 signaling in mouse skin cancer. Nutrition Research and Practice, 7, 439–445. Kanadaswami, C., Lee, L. T., Lee, P. P., Hwang, J. J., Ke, F. C., Huang, Y. T., & Lee, M. T. (2005). The antitumor activities of flavonoids. In Vivo, 19, 895–909. Kang, J. W., Kim, J. H., Song, K., Kim, S. H., Yoon, J. H., & Kim, K. S. (2010). Kaempferol and quercetin, components of Ginkgo biloba extract (EGb 761), induce caspase‐3‐dependent apoptosis in oral cavity cancer cells. Phytotherapy Research, 24(Suppl 1), S77–S82. Kee, J. Y., Han, Y. H., Kim, D. S., Mun, J. G., Park, J., Jeong, M. Y., … Hong, S. H. (2016). Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability. Phytomedicine, 23(13), 1680–1690. Kim, G. T., Lee, S. H., Kim, J. I., & Kim, Y. M. (2014). Quercetin regulates the sestrin 2‐AMPK‐p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53‐independent manner. International Journal of Molecular Medicine, 33(4), 863–869. Lee, J., Han, S. I., Yun, J. H., & Kim, J. H. (2015). Quercetin 3‐O‐glucoside suppresses epidermal growth factor‐induced migration by inhibiting EGFR signaling in pancreatic cancer cells. Tumour Biology, 36, 9385–9393. Lee, J., Lee, J., Kim, S. J., & Kim, J. H. (2016). Quercetin‐3‐O‐glucoside suppresses pancreatic cancer cell migration induced by tumor‐deteriorated growth factors in vitro. Oncology Reports, 35, 2473–2479. Lee, J. H., Lee, H. B., Jung, G. O., Oh, J. T., Park, D. E., & Chae, K. M. (2013). Effect of quercetin on apoptosis of PANC‐1 cells. Journal of the Korean Surgical Society, 85, 249–260. Lee, S. H., Lee, E. J., Min, K. H., Hur, G. Y., Lee, S. H., Lee, S. Y., … Lee, S. Y. (2015). Quercetin enhances chemosensitivity to gemcitabine in lung cancer cells by inhibiting heat shock protein 70 expression. Clinical Lung Cancer, 16, e235–e243. Lee, W. J., Hsiao, M., Chang, J. L., Yang, S. F., Tseng, T. H., Cheng, C. W., … Chien, M. H. (2015). Quercetin induces mitochondrial‐derived apoptosis via reactive oxygen species‐mediated ERK activation in HL‐60 leukemia cells and xenograft. Archives of Toxicology, 89, 1103–1117. Lee, Y. J., Lee, D. M., & Lee, S. H. (2015). Nrf2 expression and apoptosis in quercetin‐treated malignant mesothelioma cells. Molecules and Cells, 38, 416–425. Li, J., Tang, C., Li, L., Li, R., & Fan, Y. (2016). Quercetin sensitizes glioblastoma to t‐AUCB by dual inhibition of Hsp27 and COX‐2 in vitro and in vivo. Journal of Experimental & Clinical Cancer Research, 35, 61. Li, N., Sun, C., Zhou, B., Xing, H., Ma, D., Chen, G., & Weng, D. (2014). Low concentration of quercetin antagonizes the cytotoxic effects of anti‐ neoplastic drugs in ovarian cancer. PLoS One, 9, e100314. Kim, G. T., Lee, S. H., & Kim, Y. M. (2013). Quercetin regulates sestrin 2‐ AMPK‐mTOR signaling pathway and induces apoptosis via increased intracellular ROS in HCT116 colon cancer cells. Journal of Cancer Prevention, 18, 264–270. Li, Q. C., Liang, Y., Hu, G. R., & Tian, Y. (2016). Enhanced therapeutic efficacy and amelioration of cisplatin‐induced nephrotoxicity by quercetin in 1,2‐dimethyl hydrazine‐induced colon cancer in rats. Indian Journal of Pharmacology, 48(2), 168–171. Kim, H., Moon, J. Y., Ahn, K. S., & Cho, S. K. (2013). Quercetin induces mitochondrial mediated apoptosis and protective autophagy in human glioblastoma U373MG cells. Oxidative Medicine and Cellular Longevity, 2013, 596496, 1–10. Li, S. Z., Qiao, S. F., Zhang, J. H., & Li, K. (2015). Quercetin increase the chemosensitivity of breast cancer cells to doxorubicin via PTEN/Akt pathway. Anticancer Agents in Medicinal Chemistry, 15, 1185–1189. Kim, J. H., Kim, M. J., Choi, K. C., & Son, J. (2016). Quercetin sensitizes pancreatic cancer cells to TRAIL‐induced apoptosis through JNK‐mediated cFLIP turnover. The International Journal of Biochemestry & Cell Biology, 78, 327–334. Kim, M. C., Lee, H. J., Lim, B., Ha, K. T., Kim, S. Y., So, I., & Kim, B. J. (2014). Quercetin induces apoptosis by inhibiting MAPKs and TRPM7 channels in AGS cells. International Journal of Molecular Medicine, 33, 1657–1663. Kim, Y., Kim, W. J., & Cha, E. J. (2011). Quercetin‐induced growth inhibition in human bladder cancer cells is associated with an increase in Ca‐activated K channels. Korean Journal of Physiology and Pharmacology, 15, 279–283. Klimaszewska‐Wiśniewska, A., Hałas‐Wiśniewska, M., Izdebska, M., Gagat, M., Grzanka, A., & Grzanka, D. (2017). Antiproliferative and antimetastatic action of quercetin on A549 non‐small cell lung cancer cells through its effect on the cytoskeleton. Acta Histochemica, 119, 99–112. Li, W., Liu, M., Xu, Y. F., Feng, Y., Che, J. P., Wang, G. C., & Zheng, J. H. (2014). Combination of quercetin and hyperoside has anticancer effects on renal cancer cells through inhibition of oncogenic microRNA‐27a. Oncology Reports, 31, 117–124. Li, W., Zhao, Y., Tao, B., & Zhang, Y. (2014). Effects of quercetin on hedgehog signaling in chronic myeloid leukemia KBM7 cells. Chinese Journal of Integrative Medicine, 20, 776–781. Li, X., Wang, X., Zhang, M., Li, A., Sun, Z., & Yu, Q. (2014). Quercetin potentiates the antitumor activity of rituximab in diffuse large B‐cell lymphoma by inhibiting STAT3 pathway. Cell Biochemistry and Biophysics, 70, 1357–1362. Liang, W., Li, X., Li, C., Liao, L., Gao, B., Gan, H., … Chen, X. (2011). Quercetin‐mediated apoptosis via activation of the mitochondrial‐ dependent pathway in MG‐63 osteosarcoma cells. Molecular Medicine Reports, 4(5), 1017–1023. Kuhar, M., Sen, S., & Singh, N. (2006). Role of mitochondria in quercetin‐ enhanced chemotherapeutic response in human non‐small cell lung carcinoma H‐520 cells. Anticancer Research, 26, 1297–1303. Liao, H., Bao, X., Zhu, J., Qu, J., Sun, Y., Ma, X., … Zhen, Y. (2015). O‐ Alkylated derivatives of quercetin induce apoptosis of MCF‐7 cells via a caspase‐independent mitochondrial pathway. Chemico‐Biological Interactions, 242, 91–98. Lai, W. W., Hsu, S. C., Chueh, F. S., Chen, Y. Y., Yang, J. S., Lin, J. P., … Chung, J. G. (2013). Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF‐κB and matrix metalloproteinase‐2/ ‐9 signaling pathways. Anticancer Research, 33, 1941–1950. Lin, T. H., Hsu, W. H., Tsai, P. H., Huang, Y. T., Lin, C. W., Chen, K. C., … Cheng, C. H. (2017). Dietary flavonoids, luteolin and quercetin, inhibit invasion of cervical cancer by reduction of UBE2S through epithelial‐ mesenchymal transition signaling. Food & Function, 8, 1558–1568. Lam, T. K., Shao, S., Zhao, Y., Marincola, F., Pesatori, A., Bertazzi, P. A., … Landi, M. T. (2012). Influence of quercetin‐rich food intake on Lipworth, L., Tarone, R. E., & McLaughlin, J. K. (2006). The epidemiology of renal cell carcinoma. The Journal of Urology, 176, 2353–2358. RAUF 20 Liu, S. Y., & Zheng, P. S. (2013). High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer. Oncotarget, 4, 2462–2475. Liu, Y., Tang, Z.‐G., Lin, Y., Qu, X. G., Lv, W., Wang, G. B., & Li, C. L. (2017). Effects of quercetin on proliferation and migration of human glioblastoma U251 cells. Biomedicine & Pharmacotherapy, 92, 33–38. Liu, Y., Wu, Y. M., & Zhang, P. Y. (2015). Protective effects of curcumin and quercetin during benzo(a)pyrene induced lung carcinogenesis in mice. European Review for Medical and Pharmacological Sciences, 19, 1736–1743. Long, Q., Xiel, Y., Huang, Y., Wu, Q., Zhang, H., Xiong, S., … Gong, C. (2013). Induction of apoptosis and inhibition of angiogenesis by PEGylated liposomal quercetin in both cisplatin‐sensitive and cisplatin‐resistant ovarian cancers. Journal of Biomedical Nanotechnology, 9, 965–975. Luo, C. L., Liu, Y. Q., Wang, P., Song, C. H., Wang, K. J., Dai, L. P., … Ye, H. (2016). The effect of quercetin nanoparticle on cervical cancer progression by inducing apoptosis, autophagy, and anti‐proliferation via JAK2 suppression. Biomedicine & Pharmacotherapy, 82, 595–605. Lv, L., Liu, C., Chen, C., Yu, X., Chen, G., Shi, Y., … Li, G. (2016). Quercetin and doxorubicin co‐encapsulated biotin receptor‐targeting nanoparticles for minimizing drug resistance in breast cancer. Oncotarget, 7, 32184–32199. Ma, Y., Jin, Z., Huang, J., Zhou, S., Ye, H., Jiang, S., & Yu, K. (2014). Quercetin suppresses the proliferation of multiple myeloma cells by down‐ regulating IQ motif‐containing GTPase activating protein 1 expression and extracellular signal‐regulated kinase activation. Leukemia & Lymphoma, 55, 2597–2604. Maciejczyk, A., & Surowiak, P. (2013). Quercetin inhibits proliferation and increases sensitivity of ovarian cancer cells to cisplatin and paclitaxel. Ginekologia Polska, 84, 590–595. Mandal, A. K., Ghosh, D., Sarkar, S., Ghosh, A., Swarnakar, S., & Das, N. (2014). Nanocapsulated quercetin downregulates rat hepatic MMP‐ 13 and controls diethylnitrosamine‐induced carcinoma. Nanomedicine, 9, 2323–2337. Martin, K. R. (2006). Targeting apoptosis with dietary bioactive agents. Experimental Biology and Medicine, 231, 117–129. ET AL. Mutlu Altundag, E., Tolga, K., Mine, Y. A., Karademir, B., Koçtürk, S., Taga, Y., & Suha, Y. A. (2016). Quercetin‐induced cell death in human papillary thyroid cancer (B‐CPAP) cells. Journal of Thyroid Research, 2016. 9843675 Nabavi, S. F., Nabavi, S. M., Mirzaei, M., & Moghaddam, A. H. (2012). Protective effect of quercetin against sodium fluoride induced oxidative stress in rat's heart. Food Function, 3, 437–441. Naghavi, M., Wang, H., Lozano, R., Davis, A., Liang, X., Zhou, M., … Murry, C. J. L. (2015). Global, regional, and national age‐sex specific all‐cause and cause‐specific mortality for 240 causes of death, 1990–2013: A systematic analysis for the global burden of disease study 2013. Lancet, 385, 117–171. Nair, P., Malhotra, A., & Dhawan, D. K. (2015). Curcumin and quercetin trigger apoptosis during benzo(a)pyrene‐induced lung carcinogenesis. Molecular and Cellular Biochemistry, 400, 51–56. NCI. Colon cancer treatment. Retrieved 29 June 2014. NCI. Adult Primary Liver Cancer Treatment (PDQ®)—Patient version. NCI. 6 July 2016. Retrieved 29 September 2016. Nessa, M. U., Beale, P., Chan, C., Yu, J. Q., & Huq, F. (2011). Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumor models. Anticancer Research, 31, 3789–3797. Nguyen, L. T., Lee, Y. H., Sharma, A. R., Park, J. B., Jagga, S., Sharma, G., … Nam, J. S. (2017). Quercetin induces apoptosis and cell cycle arrest in triple‐negative breast cancer cells through modulation of Foxo3a activity. The Korean Journal of Physiology & Pharmacology, 21, 205–213. Nwaeburu, C. C., Bauer, N., Zhao, Z., Abukiwan, A., Gladkich, J., Benner, A., & Herr, I. (2016). Up‐regulation of microRNA Let‐7c by quercetin inhibits pancreatic cancer progression by activation of Numbl. Oncotarget, 7, 58367–58380. Ojesina, A. I., Lichtenstein, L., Freeman, S. S., Pedamallu, C. S., Imaz‐ Rosshandler, I., Pugh, T. J., … Meyerson, M. (2014). Landscape of genomic alterations in cervical carcinomas. Nature, 506, 371–375. Oršolić, N., & Car, N. (2014). Quercetin and hyperthermia modulate cisplatin‐induced DNA damage in tumor and normal tissues in vivo. Tumour Biology, 35, 6445–6454. Maso, V., Calgarotto, A. K., Franchi, G. C., Nowill, A. E., Filho, P. L., Vassallo, J., & Saad, S. T. O. (2014). Multitarget effects of quercetin in leukemia. Cancer Prevention Research, 7, 1240–1250. Oršolić, N., Karač, I., Sirovina, D., Kukolj, M., Kunštić, M., Gajski, G., … Štajcar, D. (2016). Chemotherapeutic potential of quercetin on human bladder cancer cells. Journal of Environmental Science and Health. Part a, Toxic/ Hazardous Substances & Environmental Engineering, 51, 776–781. Maurya, A. K., & Vinayak, M. (2015). Anticarcinogenic action of quercetin by downregulation of phosphatidylinositol 3‐kinase (PI3K) and protein kinase C (PKC) via induction of p53 in hepatocellular carcinoma (HepG2) cell line. Molecular Biology Reports, 42, 1419–1429. Paller, C. J., Kanaan, Y. M., Beyene, D. A., Naab, T. J., Copeland, R. L., Tsai, H. L., … Hudson, T. S. (2015). Risk of prostate cancer in African‐American men: Evidence of mixed effects of dietary quercetin by serum vitamin D status. AA men. Prostate, 75, 1376–1383. Meng, F. D., Li, Y., Tian, X., Ma, P., Sui, C. G., Fu, L. Y., & Jiang, Y. H. (2015). Synergistic effects of snail and quercetin on renal cell carcinoma Caki‐2 by altering AKT/mTOR/ERK1/2 signaling pathways. International Journal of Clinical and Experimental Pathology, 8, 6157–6168. Pan, H. C., Jiang, Q., Yu, Y., Mei, J. P., Cui, Y. K., & Zhao, W. J. (2015). Quercetin promotes cell apoptosis and inhibits the expression of MMP‐9 and fibronectin via the AKT and ERK signaling pathways in human glioma cells. Neurochemistry International, 80, 60–71. Minaei, A., Sabzichi, M., Ramezani, F., Hamishehkar, H., & Samadi, N. (2016). Co‐delivery with nano‐quercetin enhances doxorubicin‐mediated cytotoxicity against MCF‐7 cells. Molecular Biology Reports, 43, 99–105. Park, M. H., & Min do, S. (2011). Quercetin‐induced downregulation of phospholipase D1 inhibits proliferation and invasion in U87 glioma cells. Biochemical and Biophysical Research Communications, 412, 710–715. Moon, J. H., Eo, S. K., Lee, J. H., & Park, S. Y. (2015). Quercetin‐induced autophagy flux enhances TRAIL‐mediated tumor cell death. Oncology Reports, 34, 375–381. Mukherjee, A., & Khuda‐Bukhsh, A. R. (2015). Quercetin down‐regulates IL‐6/STAT‐3 signals to induce mitochondrial‐mediated apoptosis in a nonsmall‐cell lung‐cancer cell line A549. Journal of Pharmacopuncture, 18, 19–26. Murakami, A., Ashida, H., & Terao, J. (2008). Multitargeted cancer prevention by quercetin. Cancer Letters, 269, 315–325. Mutlu Altundag, E., Mine Yilmaz, A., Kasaci, T., Corek, C., Taga, Y., & Suha Yalçin, A. (2014). The role of HSP90 in Quercetin‐induced apoptosis in human papillary thyroid (B‐CPAP) cancer cells. Free Radical Biology & Medicine, 75(Suppl 1), S43. Parvaresh, A., Razavi, R., Rafie, N., Ghiasvand, R., Pourmasoumi, M., & Miraghajani, M. (2016). Quercetin and ovarian cancer: An evaluation based on a systematic review. Journal of Research in Medical Sciences, 21, 34. Pozsgai, E., Bellyei, S., Cseh, A., Boronkai, A., Racz, B., Szabo, A., … Hocsak, E. (2013). Quercetin increases the efficacy of glioblastoma treatment compared to standard chemoradiotherapy by the suppression of PI‐3‐ kinase‐Akt pathway. Nutrition and Cancer, 65, 1059–1066. Pratheeshkumar, P., Son, Y. O., Divya, S. P., Wang, L., Turcios, L., Roy, R. V., … Shi, X. (2017). Quercetin inhibits Cr (VI)‐induced malignant cell transformation by targeting miR‐21‐PDCD4 signaling pathway. Oncotarget, 8, 52118–52131. Priyadarsini, R. V., Murugan, R. S., Maitreyi, S., Ramalingam, K., Karunagaran, D., & Nagini, S. (2010). The flavonoid quercetin induces cell cycle arrest and mitochondria‐mediated apoptosis in human RAUF ET AL. cervical cancer (HeLa) cells through p53 induction and NF‐κB inhibition. European Journal of Pharmacology, 649(2010), 84–91. Priyadarsini, R. V., & Nagini, S. (2012). Quercetin suppresses cytochrome P450 mediated ROS generation and NFκB activation to inhibit the development of 7,12‐dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinomas. Free Radical Rearch, 46(1), 41–49. Priyadarsini, R. V., Vinothini, G., Murugan, R. S., Manikandan, P., & Nagini, S. (2011). The flavonoid quercetin modulates the hallmark capabilities of hamster buccal pouch tumors. Nutrition and Cancer, 63, 218–226. Qin, Y., He, L. Y., Chen, Y., Wang, W. Y., Zhao, X. H., & Wu, M. Y. (2012). Quercetin affects leptin and its receptor in human gastric cancer MGC‐803 cells and JAK‐STAT pathway. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 28(1), 12–16. Quagliariello, V., Armenia, E., Aurilio, C., Rosso, F., Clemente, O., de Sena, G., … Barbarisi, A. (2016). New treatment of medullary and papillary human thyroid cancer: Biological effects of hyaluronic acid hydrogel loaded with quercetin alone or in combination to an inhibitor of aurora kinase. The Journal of Cellular Physiology, 231, 1784–1795. Rafiq, R. A., Quadri, A., Nazir, L. A., Peerzada, K., Ganai, B. A., & Tasduq, S. A. (2015). A potent inhibitor of phosphoinositide 3‐kinase (PI3K) and mitogen activated protein (MAP) kinase signalling. Quercetin (3,3′,4′,5,7‐pentahydroxyflavone) promotes cell death in ultraviolet (UV)‐B‐irradiated B16F10 melanoma cells. PLoS One, 10, e0131253. 21 through inhibition of signal transducer and activator of transcription 3 signaling in HER2‐overexpressing BT‐474 breast cancer cells. Oncology Reports, 36, 31–42. Seyed, M. A., Jantan, I., Bukhari, S. N. A., & Vijayaraghavan, K. (2016). A comprehensive review on the chemotherapeutic potential of piceatannol for cancer treatment, with mechanistic insights. Journal of Agricultural and Food Chemistry, 64, 725–737. Sharma, V., Kumar, L., Mohanty, S. K., Maikhuri, J. P., Rajender, S., & Gupta, G. (2016). Sensitization of androgen refractory prostate cancer cells to anti‐androgens through re‐expression of epigenetically repressed androgen receptor—Synergistic action of quercetin and curcumin. Molecular and Cellular Endocrinology, 431, 12–23. Shen, X., Si, Y., Wang, Z., Wang, J., Guo, Y., & Zhang, X. (2016). Quercetin inhibits the growth of human gastric cancer stem cells by inducing mitochondrial‐dependent apoptosis through the inhibition of PI3K/ Akt signaling. International Journal of Molecular Medicine, 38, 619–626. Shih, H., Pickwell, G. V., & Quattrochi, L. C. (2000). Differential effects of flavonoid compounds on tumor promoter‐induced activation of the human CYP1A2 enhancer. Archives of Biochemistry, 373, 287–294. Song, L. M., Wang, G. D., Wang, H. P., & Xing, N. Z. (2016). Effect of 2‐ methoxyestradiol combined with quercetin on prostate cancer in vitro. Zhonghua Yi Xue Za Zhi, 96, 95–99. Ranganathan, S., Halagowder, D., & Sivasithambaram, N. D. (2015). Quercetin suppresses twist to induce apoptosis in MCF‐7 breast cancer cells. PLoS One, 10, e0141370. Sonoki, H., Sato, T., Endo, S., Matsunaga, T., Yamaguchi, M., Yamazaki, Y., … Ikari, A. (2015). Quercetin decreases claudin‐2 expression mediated by up‐regulation of microRNA miR‐16 in lung adenocarcinoma A549 cells. Nutrients, 7, 4578–4592. Refolo, M. G., D'Alessandro, R., Malerba, N., Laezza, C., Bifulco, M., Messa, C., … Tutino, V. (2015). Anti‐proliferative and pro apoptotic effects of flavonoid quercetin are mediated by CB1 receptor in human colon cancer cell Lines. Journal of Cellular Physiology, 230(12), 2973–2980. Srinivasan, A., Thangavel, C., Liu, Y., Shoyele, S., den, R. B., Selvakumar, P., & Lakshmikuttyamma, A. (2016). Quercetin regulates β‐catenin signaling and reduces the migration of triple negative breast cancer. Molecular Carcinogenesis, 55, 743–756. Ren, M. X., Deng, X. H., Ai, F., Yuan, G. Y., & Song, H. Y. (2015). Effect of quercetin on the proliferation of the human ovarian cancer cell line SKOV‐3 in vitro. Experimental and Therapeutic Medicine, 10(2), 579–583. Steiner, J., Davis, J., McClellan, J., Enos, R. T., Carson, J. A., Fayad, R., … Murphy, E. A. (2014). Dose‐dependent benefits of quercetin on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer. Cancer Biology & Therapy, 15, 1456–1467. Rivera, R. A., Castillo‐Pichardo, L., Gerena, Y., & Dharmawardhane, S. (2016). Anti‐breast cancer potential of quercetin via the akt/ampk/ mammalian target of rapamycin (mTOR) signaling cascade. PLoS One, 11, e0157251. Su, Q., Peng, M., Zhang, Y., Xu, W., Darko, K. O., Tao, T., … Yang, X. (2016). Quercetin induces bladder cancer cells apoptosis by activation of AMPK signaling pathway. American Journal of Cancer Research, 6, 498–508. Robbins, R. J., & Schlumberger, M. J. (2005). The evolving role of 131I for the treatment of differentiated thyroid carcinoma. Journal of Nuclear Medicine, 46, 28S–37S. Saleem, T. H., Attya, A. M., Ahmed, E. A., Ragab, S. M. M., Abdallah, M. A. A., & Omar, H. M. (2015). Possible protective effects of quercetin and sodium gluconate against colon cancer induction by dimethylhydrazine in mice. Asian Pacific Journal of Cancer Prevention, 16, 5823–5828. Sanchez‐Gonzalez, P. D., Lopez‐Hernandez, F. J., Perez‐Barriocanal, F., Morales, A. I., & Lopez‐Novoa, J. M. (2011). Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti‐tumour activity. Nephrology Dialysis Transplantation, 26, 3484–3495. Sang, D. P., Li, R. J., & Lan, Q. (2014). Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27. Acta Pharmacoginica Sinica, 35, 832–838. Santos, B. L., Oliveira, M. N., Coelho, P. L., Pitanga, B. P., da Silva, A. B., Adelita, T., … Costa, S. L. (2015). Flavonoids suppress human glioblastoma cell growth by inhibiting cell metabolism, migration, and by regulating extracellular matrix proteins and metalloproteinases expression. Chemico‐Biological Interactions, 242, 123–138. Sarkar, A., Ghosh, S., Chowdhury, S., Pandey, B., & Sil, P. C. (2016). Targeted delivery of quercetin loaded mesoporous silica nanoparticles to the breast cancer cells. Biochimica et Biophysica Acta, 1860, 2065–2075. Sudan, S., & Rupasinghe, H. V. (2015). Antiproliferative activity of long chain acylated esters of quercetin‐3‐O‐glucoside in hepatocellular carcinoma HepG2 cells. Experimental Biology and Medicine, 240, 1452–1464. Suksiriworapong, J., Phoca, K., Ngamsom, S., Sripha, K., Moongkarndi, P., & Junyaprasert, V. B. (2016). Comparison of poly (ε‐caprolactone) chain lengths of poly (ε‐caprolactone)‐co‐d‐α‐tocopheryl‐poly (ethylene glycol) 1000 succinate nanoparticles for enhancement of quercetin delivery to SKBR3 breast cancer cells. European Journal of Pharmaceutics and Biopharmaceutics, 101, 15–24. Tao, S. F., He, H. F., & Chen, Q. (2015). Quercetin inhibits proliferation and invasion acts by up‐regulating miR‐146a in human breast cancer cells. Molecular and Cellular Biochemistry, 402, 93–100. Waizenegger, J., Lenze, D., Luckert, C., Seidel, A., Lampen, A., & Hessel, S. (2015a). Dose‐dependent induction of signaling pathways by the flavonoid quercetin in human primary hepatocytes: A transcriptomic study. Molecular Nutrition & Food Research, 59, 1117–1129. Wang, G., Wang, J. J., Chen, X. L., Du, S. M., Li, D. S., Pei, Z. J., Lan, H., & Wu, L. B. (2013). The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome‐induced C6 glioma cell death. Cell Death & Disease, 4, e746. Wang, H., Yuan, Z., Chen, Z., Yao, F., Hu, Z., & Wu, B. (2014). Effect of quercetin on glioma cell U87 apoptosis and feedback regulation of MDM2‐p53. Nan Fang Yi Ke Da Xue Xue Bao, 34, 686–689. Sekeroğlu, Z. A., & Sekeroğlu, V. (2012). Effects of Viscum album L. extract and quercetin on methotrexate‐induced cyto‐genotoxicity in mouse bone‐marrow cells. Mutation Research, 746, 56–59. Wang, J., Zhang, Y. Y., Cheng, J., Zhang, J. L., & Li, B. S. (2015). Preventive and therapeutic effects of quercetin on experimental radiation induced lung injury in mice. Asian Pacific Journal of Cancer Prevention, 16, 2909–2914. Seo, H. S., Ku, J. M., Choi, H. S., Choi, Y. K., Woo, J. K., Kim, M., … Ko, S. G. (2016). Quercetin induces caspase‐dependent extrinsic apoptosis Wang, K., Liu, R., Li, J., Mao, J., Lei, Y., Wu, J., … Wei, Y. (2011). Quercetin induces protective autophagy in gastric cancer cells: Involvement of RAUF 22 Akt‐mTOR‐ and hypoxia‐induced factor 1α‐mediated signaling. Autophagy, 7, 966–978. Wang, P., Henning, S. M., Heber, D., & Vadgama, J. V. (2015). Sensitization to docetaxel in prostate cancer cells by green tea and quercetin. The Journal of Nutritional Biochemistry, 26, 408–415. Wang, P., Henning, S. M., Magyar, C. E., Elshimali, Y., Heber, D., & Vadgama, J. V. (2016). Green tea and quercetin sensitize PC‐3 xenograft prostate tumors to docetaxel chemotherapy. Journal of Experimental & Clinical Cancer Research, 35, 73. Wang, P., Phan, T., Gordon, D., Chung, S., Henning, S. M., & Vadgama, J. V. (2015). Arctigenin in combination with quercetin synergistically enhances the antiproliferative effect in prostate cancer cells. Molecular Nutrition & Food Research, 59, 250–261. Wang, Y., Han, A., Chen, E., Singh, R. K., Chichester, C. O., Moore, R. G., … Vorsa, N. (2015). The cranberry flavonoids PAC DP‐9 and quercetin aglycone induce cytotoxicity and cell cycle arrest and increase cisplatin sensitivity in ovarian cancer cells. International Journal of Oncology, 46, 1924–1934. Wang, Y., Zhang, W., Lv, Q., Zhang, J., & Zhu, D. (2016). The critical role of quercetin in autophagy and apoptosis in HeLa cells. Tumour Biology, 37, 925–929. Warnakulasuriya, S. N., Ziaullah, & Rupasinghe, H. P. (2016). Novel long chain fatty acid derivatives of quercetin‐3‐O‐glucoside reduce cytotoxicity induced by cigarette smoke toxicants in human fetal lung fibroblasts. European Journal of Pharmacology, 781, 128–138. Wei, L., Liu, J. J., Cao, J., Du, N. C., Ji, L. N., & Yang, X. L. (2012). Role of autophagy in quercetin‐induced apoptosis in human bladder carcinoma BIU‐87 cells. Zhonghua Zhong Liu Za Zhi, 34, 414–418. Xiang, T., Fang, Y., & Wang, S. X. (2014). Quercetin suppresses HeLa cells by blocking PI3K/Akt pathway. Journal of Huazhong University of Science and Technology. Medical Sciences, 34, 740–744. Xie, X., Yin, J., Jia, Q., Wang, J., Zou, C., Brewer, K. J., … Shen, J. (2011). Quercetin induces apoptosis in the methotrexate‐resistant osteosarcoma cell line U2‐OS/MTX300 via mitochondrial dysfunction and dephosphorylation of Akt. Oncology Reports, 26, 687–693. Xingyu, Z., Peijie, M., Dan, P., Youg, W., Daojun, W., Xinzheng, C., … Yangrong, S. (2016). Quercetin suppresses lung cancer growth by targeting Aurora B kinase. Cancer Medicine, 5, 3156–3165. Xu, G., Shi, H., Ren, L., Gou, H., Gong, D., Gao, X., & Huang, N. (2015). Enhancing the anti‐colon cancer activity of quercetin by self‐assembled micelles. International Journal of Nanomedicine, 10, 2051–2063. Yamazaki, S., Miyoshi, N., Kawabata, K., Yasuda, M., & Shimoi, K. (2014). Quercetin‐3‐O‐glucuronide inhibits noradrenaline‐promoted invasion of MDA‐MB‐231 human breast cancer cells by blocking β₂‐adrenergic signaling. Archives of Biochemistry and Biophysics, 557, 18–27. Yang, F., Song, L., Wang, H., Wang, J., Xu, Z., & Xing, N. (2015). Combination of quercetin and 2‐methoxyestradiol enhances inhibition of human prostate cancer LNCaP and PC‐3 cells xenograft tumor growth. PLoS One, 10, e0128277. Yang, F. Q., Liu, M., Li, W., Che, J. P., Wang, G. C., & Zheng, J. H. (2015). Combination of quercetin and hyperoside inhibits prostate cancer cell growth and metastasis via regulation of microRNA‐21. Molecular Medicine Reports, 11, 1085–1092. Yang, Z., Liu, Y., Liao, J., Gong, C., Sun, C., Zhou, X., … Chen, G. (2015). Quercetin induces endoplasmic reticulum stress to enhance cDDP cytotoxicity in ovarian cancer: Involvement of STAT3 signaling. The FEBS Journal, 282, 1111–1125. Yi, L., Zongyuan, Y., Cheng, G., Lingyun, Z., Guilian, Y., & Wei, G. (2014). Quercetin enhances apoptotic effect of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer‐binding protein homologous protein (CHOP)‐death receptor 5 pathway. Cancer Science, 105, 520–527. View publication stats ET AL. Yin, J., Xie, X., Jia, Q., Wang, J., Huang, G., Zou, C., & Shen, J. (2012). Effect and mechanism of quercetin on proliferation and apoptosis of human osteosarcoma cell U‐2OS/MTX300. Zhongguo Zhong Yao Za Zhi, 37, 611–614. Youn, H., Jeong, J. C., Jeong, Y. S., Kim, E. J., & Um, S. J. (2013). Quercetin potentiates apoptosis by inhibiting nuclear factor‐kappaB signaling in H460 lung cancer cells. Biological and Pharmaceutical Bulletin, 36, 944–951. Yu, Z. J., He, L. Y., Chen, Y., Wu, M. Y., Zhao, X. H., & Wang, Z. Y. (2009). Effects of quercetin on the expression of VEGF‐C and VEGFR‐3 in human cancer MGC‐803 cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 25, 678–680. Yuan, Z., Wang, H., Hu, Z., Huang, Y., Yao, F., Sun, S., & Wu, B. (2015). Quercetin inhibits proliferation and drug resistance in KB/VCR oral cancer cells and enhances its sensitivity to vincristine. Nutrition and Cancer, 67, 126–136. Zamin, L. L., Filippi‐Chiela, E. C., Vargas, J., Demartini, D. R., Meurer, L., Souza, A. P., … Lenz, G. (2014). Quercetin promotes glioma growth in a rat model. Food and Chemical Toxicology, 63, 205–211. Zhang, J. Y., Lin, M. T., Zhou, M. J., Yi, T., Tang, Y. N., Tang, S. L., … Chen, H. B. (2015). Combinational treatment of curcumin and quercetin against gastric cancer MGC‐803 cells in vitro. Molecules, 20, 11524–11534. Zhang, W., & Zhang, F. (2009). Effects of quercetin on proliferation, apoptosis, adhesion and migration, and invasion of HeLa cells. European Journal of Gynaecological Oncology, 30, 60–64. Zhang, W. T., Zhang, W., Zhong, Y. J., Lü, Q. Y., & Cheng, J. (2013). Impact of quercetin on the expression of heparanase in cervical cancer cells. Zhonghua Fu Chan Ke Za Zhi, 48, 198–203. Zhang, X., Guo, Q., Chen, J., & Chen, Z. (2015). Quercetin enhances cisplatin sensitivity of human osteosarcoma cells by modulating microRNA‐217‐KRAS axis. Molecules and Cells, 38, 638–642. Zhang, X. A., Zhang, S., Yin, Q., & Zhang, J. (2015). Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor‐ kappa B Pathway. Pharmacognosy Magazine, 11, 404–409. Zhao, J., Liu, J., Wei, T., Ma, X., Cheng, Q., Huo, S., … Liang, X. J. (2017). Quercetin‐loaded nanomicelles to circumvent human castration‐resistant prostate cancer in vitro and in vivo. Nanoscale, 8, 5126–5138. Zhao, P., Mao, J. M., Zhang, S. Y., Zhou, Z. Q., Tan, Y., & Zhang, Y. (2014). Quercetin induces HepG2 cell apoptosis by inhibiting fatty acid biosynthesis. Oncology Letters, 8, 765–769. Zhao, X., Wang, Q., Yang, S., Chen, C., Li, X., Liu, J., … Cai, D. (2016). Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer. European Journal of Pharmacology, 781, 60–68. Zhao, X., & Zhang, J. (2015). Mechanisms for quercetin in prevention of lung cancer cell growth and metastasis. Zhong Nan Da Xue Xue Bao. Yi Xue Ban, 40, 592–597. Zhao, Y., Fan, D., Zheng, Z. P., Li, E. T. S., Chen, F., Cheng, K. W., & Wang, M. (2017). 8‐C‐(E‐phenylethenyl) quercetin from onion/beef soup induces autophagic cell death in colon cancer cells through ERK activation. Molecular Nutrition &Food Research, 61(2). https://doi.org/ 10.1002/mnfr.201600437 Zhou, J., Gong, J., Ding, C., & Chen, G. (2015). Quercetin induces the apoptosis of human ovarian carcinoma cells by upregulating the expression of microRNA‐145. Molecular Medicine Reports, 12, 3127–3131. Zhu, X., Zeng, X., Zhang, X., Cao, W., Wang, Y., Chen, H., … Shi, X. (2016). The effects of quercetin‐loaded PLGA‐TPGS nanoparticles on ultraviolet B‐induced skin damages in vivo. Nanomedicine, 12, 623–632. How to cite this article: Rauf A, Imran M, Khan IA, et al. Anticancer potential of quercetin: A comprehensive review. Phytotherapy Research. 2018;1–22. https://doi.org/10.1002/ ptr.6155