Omcl2021 9068850

Hindawi
Oxidative Medicine and Cellular Longevity

Volume 2021, Article ID 9068850, 31 pages
https://doi.org/10.1155/2021/9068850
Review Article
Roles of Therapeutic Bioactive Compounds in
Hepatocellular Carcinoma
Divya Jain,1 Yogesh Murti,2 Wasi Ullah Khan,3 Rajib Hossain,4 Mohammad Nabil Hossain,5
Krishn Kumar Agrawal,6 Rana Azeem Ashraf,7 Muhammad Torequl Islam,4
Pracheta Janmeda ,1 Yasaman Taheri ,8 Mohammed M. Alshehri ,9
Sevgi Durna Daştan,10,11 Balakyz Yeskaliyeva,12 Aliya Kipchakbayeva,12
Javad Sharifi-Rad ,8 and William C. Cho 13
1
Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan, India
2
Institute of Pharmaceutical Research, GLA University, Mathura, India
3
Key Laboratory for Sustainable Utilization of Tropical Bioresource, College of Tropical Crops Hainan University, Haikou, China
4
Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University,
Dhaka, Bangladesh
5
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China
6
Faculty of Pharmacy, R.B.S. Engineering Technical Campus, Bichpuri, Agra, India
7
School of Pharmaceutical Science and Technology (SPST), Tianjin University, China
8
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
9
Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
10
Department of Biology, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
11
Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, 58140 Sivas, Turkey
12
Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, 050040 Almaty, Kazakhstan
13
Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, SAR, China
Correspondence should be addressed to Pracheta Janmeda; [email protected],

Javad Sharifi-Rad; javad.sharifi[email protected], and William C. Cho; [email protected]
Received 4 August 2021; Accepted 6 October 2021; Published 31 October 2021
Academic Editor: ChongDe Sun
Copyright © 2021 Divya Jain et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Hepatocellular carcinoma (HCC) is due to poor prognosis and lack of availability of effective treatment. Novel therapeutic
strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells of ROS-induced tumor-promoting
events. This review discusses the generation of ROS, the major signaling their modulation in therapeutics. We explore
some of the major pathways involved in HCC, which include the VEGF, MAPK/ERK, mTOR, FGF, and Ser/Thr kinase
pathways. In this review, we study cornerstone on natural bioactive compounds with their effect on hepatocarcinomas.
Furthermore, we focus on oxidative stress and FDA-approved signaling pathway inhibitors, along with chemotherapy and
radiotherapy enhancers which with early evidence of success. While more in vivo testing is required to confirm the
findings presented here, our findings will aid future nonclinical, preclinical, and clinical studies with these compounds, as
well as inspire medicinal chemistry scientists to conduct appropriate research on this promising natural compound and their
derivatives.
2 Oxidative Medicine and Cellular Longevity
1. Introduction ily are VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF,

and their potential forms include VEGF-A121 and VEGF-
Globally, cancer is the major cause of mortality and morbid- A165. VEGF has three main subtypes: VEGFR-1, VEGFR-
ity, which can affect almost every organ in the human body 2, and VEGFR-3. They all are embedded in the cell mem-
[1]. According to the WHO, 1 out of 6 persons die due to brane; the extracellular region has a single TM seven immu-
cancer. In 2040, it will rise up to 29.4 million cancer cases noglobulins like domains and an intracellular region having
globally per year [2]. Hepatocellular carcinoma (HCC) is a split tyrosine kinase domain [32]. They get phosphorylated
one of the most lethal cancers; in men, it is the fifth, and after the ligand binding that activates PLC-γ, which leads to
in women, it is the eighth foremost cause of cancer death activate the PKC leading to the MAPK signaling pathway
worldwide [3, 4]. There are several ways to inhibit liver can- and activates endothelial NO that promotes cell proliferation
cer such as antioxidant [5], antiproliferative [6], anti- and vascular permeability (Figure 1). It also activates the
invasive [7], apoptotic [8], antimutagenic [9], anticarcino- Rho GTPase [33, 34].
genic [10], antitumor [11], and cytotoxic activity [12]. Out of all, VEGFR-2 seems to have a significant job in
Nature is the big source of natural medicine and com- interceding practically the entirety of the known cell reac-
pounds derived from plants, animals, marines, and microbes tions to VEGFs [35]. The initiation of VEGFR-2 prompts
[13–18]. Among them, plants provide many novel antican- endothelial cells to bring about their multiplication, reloca-
cer compounds [19] such as alkaloids [20, 21], flavonoids tion, expanded endurance, and advances vascular penetra-
[22, 23], glycosides [24], saponins, tannins [25], and terpe- bility, whereas VEGFR-3 is significant for the
noids [26] which are found from a plant having antioxidant lymphangiogenesis [36]. The articulation of VEGF mRNA
and anticancer properties in a various cancer cell line, espe- in liver tumors was found in a larger part of HCC patients.
cially in a liver cancer cell line. HCC development is a mul- The rule course of HCC dispersal and metastasis is through
tistep process that may include the alteration in host gene the entry vein in the liver, and VEGF mRNA level related
expression, DNA methylation, loss of heterozygosity, and well with portal vein tumor thrombus (PVTT) development
point mutation, but still, we are lacking to determine the rate of HCC. Immunohistochemical recognized high VEGF
limiting step for initiation and progression of HCC [27]. articulation is very much separated from HCC just as
As of late, improved information on oncogenic forms regions encompassing the HCC tissues [37]. The most
and the signaling pathways that manage tumor cell multipli- immediate proof supporting the job of the VEGF pathway
cation, differentiation, angiogenesis, invasion, and metastasis in HCC originated from late advancement in treatment hin-
has prompted the recognizable proof of a few potential dering this pathway.
restorative focuses on that have driven the advancement of Bevacizumab (anti-VEGF monoclonal antibodies) are
molecularly focused on treatments [28]. These medications being tested for HCC [38], whereas sorafenib is capable of
which act straightforwardly on segments of the signaling targeting vascular endothelial growth factor receptor 2
pathways can control tumorigenesis and have demonstrated (VEGFR-2) and other proteins to inhibit the tumor angio-
clinical advantage in patients with different tumor types. genesis [39]. In two significant clinical trials, it has been
Here, we reviewed significant molecular signaling pathways reported that in the late stage, sorafenib was effective in
embroiled in the pathogenesis of HCC and phytochemicals improving the outcomes of HCC patients.
that are involved in the treatments as of now being devel-
oped and endorsed for HCC [29]. 2.2. Mitogen-Activated Protein Kinase Signaling Pathway.
The mammalian mitogen-activated protein kinase (MAPK)
2. Signaling Pathways Involved in HCC family has three members, extracellular signal-regulated
kinase (ERK), c-Jun NH2-terminal a kinase (JNK), and p38
HCC carcinogenesis is a complex multistep process that that are involved in a variety of cellular activities [40].
involves a variety of signaling cascades at the molecular level. Among them, the ERK pathway is involved in promoting
The major signaling pathways include vascular endothelial cell proliferation, migration, survival, and tumor progres-
growth factor (VEGF) pathway, mitogen-activated protein sion. In the ERK pathway ligand bind with receptor tyrosine
kinase (MAPK/ERK) pathway, Wnt/β-catenin pathway, kinase (RTKs), this triggers the tyrosine kinase domain acti-
phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian tar- vation [41]. That acts as docking sites for GRB2 and SOS
get of rapamycin (mTOR) signaling pathway, fibroblast proteins. This leads to an activation cascade of small GTPase
growth factor (FGF) pathway, enzymes reactions generating RAS, Ser/Thr kinase RAF, and MEK [42].
ROS in liver cancers, enzymatic cycle of P450, mitochondrial ERK activation can alter the various activities of tran-
dysfunction and signaling, and serine/threonine kinase scription factors and gene expression level which leads to
(AKT) pathway. alteration in cell cycle progression [43]. The phosphorylated
ERK (ERK-P) can activate c-myc that regulates cell growth
2.1. VEGF Signaling Pathway. VEGF is a critical growth fac- and cell proliferation (Figure 2) [44, 45]. Moreover, it also
tor for angiogenesis during hypervascular HCC cancer promotes the survival of cancer cells by regulating the BIM
development [30]. Deep located tumor cells are required to and MCL1 apoptotic pathways [46, 47]. The role of the
locate 100-200 μm to acquire oxygen and nutrients for sur- ERK pathway in HCC is confirmed by AZD6244 (MEK
vival and proliferation. Tumor size greater than 2 mm3 inhibitors) that block cell proliferation and promote pro-
required angiogenesis [31]. The major members of the fam- grammed cell death in liver carcinoma [48, 49].
Oxidative Medicine and Cellular Longevity 3
Extracellular matrix
Vascular permeability
VEGF-2 Rho GTPase Cellular migration
Invasion
VEGF-2-P
PLC-𝛾 PKC
MAPK No
Cell proliferation Vascular permeability
ANGIOGENESIS
Figure 1: VEGF signalling mechanism. VEGF: vascular endothelial growth factor; PLC-γ: phospholipase C gamma; PKC: protein kinase C;
MAPK: mitogen-activated protein kinase; NO: nitric oxide.
RTKs film to LPR-5, and the β-catenin demolition complex is

then inactivated [55]. This permits the unphosphorylated
S RAS β-catenin to aggregate and to move into the nucleus
O
GRB-2 S (Figure 3). This β-catenin then structures a complex with
a TCF-LEF group of DNA restricting record variables to ini-
RAF MEK1/2 tiate the TCF-LEF target gene [56]. A significant number of
PLC
the objective gene is engaged with cell multiplication, i.e.,
Proto-oncogene
cyclin D1.
PKC ERK1/2 Phosphorylated β-catenin binds with E-cadherin and
c- jun c- myc performs cell to cell adhesion that is a significant process in
the development of tumor metastasis. The researcher found
TRANSCRIPTION strong evidence of Wnt/β-catenin’s role in liver carcinoma.
Tumorigenesis
In most of the HCC cases, the level of β-catenin is overexpressed
that leads to accumulation and results in cell proliferation
Figure 2: Mitogen-activated protein kinase signaling mechanism. and inhibiting differentiation. There are likewise considered
RTK: receptor tyrosine kinase; GRB-2: growth factor receptor partner β-catenin transformations or initiation with com-
bound protein-2; SOS: Son of Sevenless; RAF: rapidly accelerated pounded HCC result, i.e., bigger tumor size, expanded vas-
fibrosarcoma; PLC: phospholipase C; PKC: protein kinase C. cular intrusion, and point mutation or deletion [57].
Such predominant addition of work transformations
Another MAPK signaling pathway includes JNK (JNK-1 normally happens at the N-terminal phosphorylation desti-
and JNK-2) activated by MKK-4 and MKK-7, and down- nations on β-catenin, including the locales phosphorylated
stream substrates include c-Jun [50]. There is strong evi- by GSK3β that control β-catenin debasement. Changes at
dence that JNK-1 increased histone H3 lysine 4 and 9 these positions disturb acknowledgment by GSK3β bringing
trimethylations, tumor size that results in the upregulation about increasingly stable β-catenin protein. In this manner,
of cell growth promoting genes [51]. Unlike ERK/JNK path- different reasons for β-catenin aggregation may exist [58].
ways, p38 are induced by MKK-3, 4, and 6 and have a sup- It has been demonstrated that the pharmacologic
pressive role in HCC [52]. The mechanism behind the p38 restraint of β-catenin diminishes the endurance of hepatoma
activity is the suppression of JNK and the negative regula- cells. Inactivation of β-catenin silencer APC prompted the
tion of cell proliferation [53]. unconstrained improvement of HCC in a mice model,
recommending the immediate commitment from actuated
2.3. Wnt/β-Catenin Signalling Pathway. Wnt ligands are cell Wnt motioning to hepatocarcinogenesis. In any case, parts
surface ligands that play a significant role in normal liver of the Wnt pathway may speak to potential restorative inter-
function. They form complexes with Frizzled receptors and cession that focuses on rewarding HCC [59].
LRP-5/LRP-6 coreceptors. β-Catenin forms a complex with
various tumor suppressor proteins like APC, axin, and 2.4. Phosphatidylinositol-3 Kinase (PI3K) Signaling Pathway.
Ser/Thr kinase GSK3β in which APC and axin proteins A phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian
make structural changes in GSK3β to phosphorylate β- target of rapamycin (mTOR) signaling pathway has a class
catenin [54]. This leads to β-catenin destruction in the cyto- to the large group of related kinases that have two subunits,
sol. Upon Wnt binding with a ligand, axin is enlisted to the i.e., catalytic and regulatory. It is an intracellular signal
mycin analog (rapalog) mTOR inhibitor administered per

Wnt receptor oral and has been approved by FDA that showed a signifi-
cant reduction in tumor growth rate by downregulating gene
expression which related to ribosomal protein S6 kinase
beta-1 (S6K1) and eIF4E-binding protein (4EBP) suppres-
Cell membrane sion and inhibits signaling downstream [63].
2.5. Fibroblast Growth Factor Pathway. Fibroblast growth

factor (FGF) ligand is a family of 20 different ligands that
APC Axin GSK-3β consist of an extracellular transmembrane domain and
intracellular tyrosine kinase domain that is associated with
tumorigenesis [64]. Many studies suggested the significant
role of FGF in the progression of chronic hepatitis. The tyro-
sine kinase domains after dimerization can activate the dif-
ferent intracellular signaling pathways [65]. FGF-substrate-
2 (FRS-2) is an important adaptor of the FGF receptor that
𝛽-Catenin
can recruit various proteins like SOS and GRB2 after the
phosphorylation to activate RAS-GTPase which promotes
the different downstream signaling like Wnt, MAPK, and
PI3K/AKT pathways as shown in Figure 4 [66]. The down-
stream signaling of FGF leads to carcinogenesis via angio-
genesis. The overexpression of FGFR1 significantly
TRANSCRIPTION accelerates the growth of HCC in the mouse model [67].
FGF8, 17, and 18 increase the HCC cell survival, and sug-
gesting a role in the progression of HCC, likewise, FGF15
also promotes hepatocellular proliferation in mice that also
Tumorigenesis contribute towards the HCC development. In addition to
this, epithelial-to-mesenchymal transition is promoted by
Figure 3: Wnt/β-catenin signaling pathway. APC: adenomatous FGFR19 that functions via the GSK3β signaling pathway
polyposis coli; GSK3β: glycogen synthase kinase 3 beta. through FGFR4 stimulation [68].
2.6. Enzyme (P450) Reactions Generating ROS in Liver

transducer enzyme that can phosphorylate the -OH group of Cancers. Human cytochrome P450s are one of the major
phosphatidyl-inositol. The p85 is a regulatory subunit of sources of ROS. It plays a very important role in maintaining
PI3K that can interrelate with phosphor-tyrosines on acti- cellular redox species balance which is mandatory for cell
vated RTKs that recruit the ligands to the plasma membrane signaling and normal cellular functions like an immune
and initiates the enzymatic activities. The lipid second mes- response [69]. Normal redox balance is very important for
senger phosphatidyl-inositol-triphosphate (PIT) is activated normal organ functioning so that any malfunction cannot
by PI3K in response to activating the PI3K. The downstream lead to various ailments like oxidative stress, aging, and car-
ligand of PI3K is AKT kinase having domain on C terminus cinogenesis. Likewise, ROS and RNS can also disrupt biolog-
that is pleckstrin homology (PH), which binds with PIT and ical functions, which lead to cellular damage and oxidative
phosphorinositide-dependent kinase 1 (PKDK1) [60]. stress [70]. In most cases, variations in structure patterns
PDK1 activates the AKT kinase activity that phosphory- of lipids, nucleic acids, and proteins are the main targets of
lates various proteins and manages cellular activities. The ROS. Oxygen radicals by some nonenzymatic oxidation of
downstream effector of AKT is mTOR that belongs to the arachidonic acid form F2-isoprostanes through lipid peroxi-
PI3K family that contains FAT-FATC domains, FRB, and dation [71]. These F2-isoprostanes not only show their bio-
catalytic kinase domains [61]. The AKT phosphorylates the logical effects but are also used as alternate markers to
TSC1/TSC2 that activates the Rheb, a small G-protein that measure ROS levels and oxidative stress [72]. Human
finally activates the mTOR for its cellular activity protein CYP2E1 has known to produce ROS through the process
translation. Excessive protein translation generally results of lipid peroxidation, and their products interact with
in abnormal cell growth and tumorigenesis. The negative DNA and cause DNA adducts [73], whereas protein modifi-
regulator of this signaling pathway is PTEN that dephos- cations through ROS are also possible particularly amino
phorylates the PIT [62]. acid cysteine modification can cause downstream signaling
In HCC pathogenesis, reduced PTEN expression has in toxic pathways leading to carcinogenesis especially HCC.
been linked with high recurrence rate, tumor stage, and ROS are generated in the mitochondria, peroxisomes,
low survival rate. In the treatment policy, the PI3K/AKT/m- cytochrome p450, and other components of the cell [74,
TOR signaling pathway is upregulated, and inhibitors could 75]. Initially, an electron is provided to O2- that further dis-
play an important role. In addition, everolimus [Afinitor, mutases to H2O2. Here, superoxide dismutase converts O2 to
RAD-001 (40-O-(2-hydroxyethyl)- rapamycin)] is a rapa- H2O2 which is a stable molecule and can cross membranes.
ing their catalytic cycle alters the redox reactions and disrupts
FGF monomer
H
P
S
the normal P450 catalytic cycle, which results in oxidative
stress leading to development of various kinds of disease.
FGFR
FGFR
FGFR
Cell membrane
FGFR
FGFR
GRB 2.8. Mitochondrial Dysfunction and Signaling. Mitochondria
FRS2
2 PLCΥ regulate the urea cycle, amino acid, iron, and fat metabolism
SO
S and produce energy required for the cell to perform all impor-
P P tant functions [80–82]. In cells, the major site for the produc-
RAS tion of ROS is mitochondrion [83]. Increased levels of ROS
production act as a clear death threat to the cells because it
PI3K
RAF directly affects the defense mechanism, the most exclusive
IP3-DAG
MAPK AKT autophagy, and plays their role as signaling molecules which
mTOR PKC-Ca+2 ultimately results in cell death either by autophagy or apopto-
ERK1/2 tic pathway (Figure 8). In each case, mobilization of various
Cell proliferation&differentiation H2O2 sensitive pathways is initiated [84]. Moreover, in starved
conditions, autophagy process increases due to elevated ROS
ANGIOGENESIS
production by mitochondria [85].
Figure 4: Fibroblast growth factor signaling pathway. GBR: growth Similar studies in obese (ob/ob) mice have also shown
factor receptor-bound; SOS: Son of Sevenless; PLCγ: phospholipase increased production of FFAs from glucose, elevated mt
C gamma; MAPK: mitogen-activated protein kinase; ERK1/2: ROS productions, and elevated levels of triglycerides [86],
extracellular signal-regulated kinase; PI3K: phospho-inositide-3- higher oxidative stress due to increased lipid peroxidation
kinase; AKT: protein kinase B; mTOR: mammalian target of while decreased hepatic mitochondrial components of
rapamycin; PKC-Ca2+: protein kinase C-Ca2+. MRC and decreased ATP levels [87]. All these mitochon-
drial changes require alterations in mitochondrial ROS
In the cytochrome chain, free radicals are formed when the levels, changes in mitophagy, biogenesis, and relevant signal-
electrons, donated by FADH and NADH, react with oxygen ing pathways of ROS.
and other electron acceptors [76] as shown in Figure 5. It also requires changes in cholesterol and GSH levels in
mitochondria. Changes in FFAs, lipid peroxidation prod-
2.7. Enzymatic Cycle of P450. Human cytochrome P450s ucts, and TNF are observed as well [88]. Oxidative stress
(CYP) are a superfamily of monooxygenases that are pri- causes ROS generation which results in the activation of cas-
marily known for the oxidation of the vast majority of xeno- cades involving PKCβ-dependent phosphorylation of
biotics in phase I metabolism helping in increasing substrate pp66shc and its movement to the matrix of mitochondria,
polarity and helping in excretion [77]. CYP generates ROS and these mitochondria are also the main target of ROS.
and how they contribute to an increase in oxidative stress.
In the very first step, the substrate (R-H) binds to the active 2.9. Serine/Threonine Kinase (AKT) Pathway. It is also known
site of the CYP enzyme via ferric iron (Fe3+) of the heme as protein kinase B (PKB) play an important role in angiogen-
thiolate group (Figure 6). In the second step, the heme thio- esis in pathological condition and tumor growth via different
late group receives one electron from the NADPH regener- Ser/Thr kinase family members like liver kinase B1 (LKB1),
ating system and CPR cytochrome peroxidase reductase calcium/calmodulin-dependent protein kinase IV (CAM-
(redox partner of CYP enzyme) and gets reduced to Fe+2. KIV), and sulfatase (SULF2). LKB1 has multiple phenotypic
This is the time when molecular oxygen binds to O2 and expressions for the regulation of cell polarity, metabolism,
CPR, then donates the second electron and reduces the Fe2 proliferation, and apoptosis. In HCC, LKB1 phosphorylate
+-
O2 complex which activates oxygen in the complex (Fe2 at Ser428 that phosphorylates AMP-activated protein kinase
+-
O2−). In the next step (H+), ions get into the active site (AMPK) microtubule affinity-regulating kinase (MARK)
by some special ion channels and cleave the O-O bond and phosphorylation leads to activation and localization of cofac-
release water. The complex (FeO2+3) then removes a proton tors like pseudokinase Ste20-related adaptor (STRADα) and
in the step from the substrate and leaves an intermediate the scaffolding protein MO25. The STRADα and MO25 form
RFe3+.OH−. In the last step, the –OH hydroxyl group is a complex that binds with the LKB1 and relocalize it from
transferred to the substrate radical and the oxidized sub- nucleus to cytoplasm and stimulate its cell proliferation and
strate is released at the end (Figure 7). The latest research angiogenesis [89]. Calcium (Ca+2) regulates various biologi-
is underway to specifically highlight the role of intermediate cal processes as a second messenger via a variety of signaling
species in various types of CYP-mediated oxidation reac- pathways. It binds to downstream effector calmodulin
tions; these intermediate species are formed during steps of (CAM) and increases the affinity toward calmodulin-kinase
the CYP 450 catalytic cycle [78]. Oxygen concentration like Ca+2±/CAM-protein kinase-IV (CAMKIV). CAMKIV
and pH are the two major factors that play an important role expression is increased in HCC and shows cell proliferation
in CYP-mediated coupling reactions [79]. and cell cycle regulation [90].
In this way, the CYP-mediated ROS-generated reaction Overexpression of calcium in HCC binds with the calmod-
through their catalytic cycle modifies the cellular compo- ulin that forms a complex with upregulated Ca+2/CAM-
nents which lead to various diseases. It is clear how CYP dur- dependent protein kinase kinase-2 (CAMKK2). Further, this
NOs
ONOO– 2O2
Arginine NO- O2
xo Uric acid
Xanthine H2O
O2
0
P45
NADPH
NADP + O2
+
NADP + H
NADPH
O2 NADPH Oxidase
O2
H+ H+ H+
I III IV V
II
NADPH FAD O2
NADP + FADH2 H2O ADP = Pi
ONOO– SOD
H2O2 OH– ATP H+
O2
NO
Figure 5: Generation of reactive oxygen species (ROS).
Role of CYPs in ROS mediated diseases
Substrate
Human diseases:
(R)
–Cancer
Oxidized
substrate –Cardiovascular
(R-0H)
–Neuro degenrative
P450 reaction
cycle
Alcoholism effects:
Reactive –Protein modification

oxygen species
(ROS) –Lipid peroxidations
–Oxidative damage
Figure 6: Cytochrome P450 contribution to human diseases caused by ROS and produced as a result of substrate metabolism by CYP 450s
which cause elevations in protein and nucleic acid levels and cause lipid modifications. These modified products further lead to lipid
peroxidation processes and also cause DNA damage which in turn causes cancer.
1 2 3
RH ⁎
+RH 4
Fe+3 Fe+3RH +e– Fe+2RH
+O2
Fe+2–O2 +e
⁎
O2
9 RH
+2H+ +2
–ROH H2O2 Fe –O–O–
RH
+ H+
R. RH
+3 +3–OH +3 +2
+ H+ Fe 5
Fe Fe Fe –O –O–OH
ROH –H2O
8 7 6
Figure 7: Summarized CYP 450 catalytic cycle. Catalytic cycle of P450s showing some critical steps where ROS are generated (shown in
red). These ROS can further cause damage to cellular components that lead to various diseases.
Oxidative stress Apoptotic Autophagic

cell death ROS
cell survival
PKC (beta)
P-p66
P-p66
Endoplasmic reticulum
Ca+2 Mitopathy
Bnip3
UIK1
Ca+2 PTP
Parkin
Fis1 (fusion)
Mitochondria
Figure 8: Signaling pathways regulating mitochondrial function.
complex stimulates the CAMKIV and AMPK that leads to STA

P
RDα CAM
stimulate angiogenesis [91]. Sulfatase 2 (SULF2) is elevated in Ca+2 SULF2
LKB1 MO
HCC that is linked with increased tumor growth, hepatoblast 25
phenotype, and a higher rate of tumor recurrence. Dephos- CAM 6-O-desulfatase
CAMMKK2
phorylation of SULF2 enzyme leads to 6-O-desulfurase that LKB1
P
acts on heparin sulfate proteoglycans (HSPGs) and releases HSPGs
the cytokines and growth factors like inflammatory media- CAMKI CAM CAMKIV
AMPK P
tors. These mediators regulate the SULf2-directed tumorigen-
esis via different pathways like hedgehog (HH), WNT, and
TGFβ. These pathways transcripts the common pathway TSC1 TSC2 P HH GLI1 TGFβ
mTOR
GLI family zinc finger 1(GLI1). SULF2-GLI1 promotes tumor Rhed
growth via heterodimerization of STAT3 that work via the GLI1
JAK/STAT signaling pathway as shown in Figure 9 [92]. ABNORMAL CELL GROWTH
Many signaling pathway inhibitors have been approved by TUMOROGENESIS
the FDA or are in clinical trials (as shown in Table 1).
Figure 9: Serine/threonine kinase (AKT) pathway. LKB1: liver
kinase B1; HSPGs: heparin sulfate proteoglycans; CAMKK2: Ca
3. Antioxidant Effect of Medicinal Plants +2/CAM-dependent protein kinase kinase-2; CAMKIV:
calcium/calmodulin-dependent protein kinase IV; SULF2:
Reactive oxygen species (ROS) is a class of reactive molecules, sulfatase 2; STRADα: Ste20-related adaptor; HH: hedgehog; GLI1:
which are generated from oxygen metabolism [105]. Further- GLI family zinc finger 1.
more, several damages occurred in cells and tissues, not only
during infections but also various degenerative disorders
including cardiovascular disease, aging, neurodegenerative cals in cells. Additionally, antioxidant enzymes (SOD, CAT,
diseases, and cancer by ROS [106, 107]. For radical detoxifi- and GPx), along with vitamin A, C, E play a provital role in
cation, human cells have defense mechanisms. In these cells, the antioxidant defense mechanisms [108–111]. In recent
superoxide dismutase (SOD) transforms superoxide into years, researchers focused on the natural phytochemicals
hydrogen peroxide and oxygen, then converted the H2O2 found in berry crops, teas, herbs, oilseeds, beans, fruits, and
into water, and toxic ROS are scavenged by catalase (CAT), vegetables, which are the potential sources of antioxidant
glutathione peroxidase (GPx), and reduce oxygen-free radi- compounds to treat several [19, 112–119].
Table 1: Clinical trials and FDA approved molecules that exert inhibitory effect for each signaling pathway.
Clinical
Compounds/ trial/ Receptor/
Chemical structure Description Inhibitor References
drugs FDA target
approved
Cl
VEGFR1,
Vatalanib N NH VEGFR2, Small-molecule tyrosine VEGF
N N Phase
(PTK787/ZK VEGFR3, kinase receptor signaling [93]
-III
222584) PDGFR-β, inhibitor pathway
c-Kit
Vatalanib
VEGF–
VEGFR- VEGF
AE-941 Phase Shark-cartilage
Structure not available binding signaling [93, 94]
(Neovastat®) -III component
MMP2, pathway
MMP9
F
F
NH NH
F
O
O Cl
VEGFR-2, Small-molecule Raf VEGF
Phase
Sorafenib PDGFR-β, kinase and tyrosine signaling [93]
-III
FLT3, c-Kit kinase inhibitor pathway
NH
N C H3
Sorafenib
O N O
F
H3 C NH N NH
Allosteric, non-ATP
FDA MAPK
Trametinib BRAF competitive small- [95, 96]
O N approved pathway
H3 C C H3 I molecule inhibitors
O
Trametinib
H3 C O
N O
NH OH
N NH
BRAFV600E Allosteric, non-ATP
F F FDA MAPK
Binimetinib or competitive small- [96]
approved pathway
BRAFV600K molecule inhibitors
Br
Binimetinib
Inactivate Wnt
Wnt/β-
signaling by
Phase I- catenin
Genistein GSK3-β upregulating the [97]
II signalling
expression of GSK3-β
pathway
and E-cadherin
Table 1: Continued.
Clinical
drugs FDA target
approved
HO O
OH O
OH
Genistein
OH
HO P O
O
O
Blocks the interaction
Wnt/β-
O
N between β-catenin and
catenin
PRI-724 Phase 1 β-Catenin its transcriptional [98, 99]
N N signalling
N CH3 coactivator CREB-
pathway
N CH3 binding protein (CBP)
O NH
PRI-724
N
HN
N
HN N Capable of inducing
N C H3 apoptosis and inhibit PI3K
USFDA
Idelalisib PI3K-δ AKT phosphorylation signaling [100, 101]
approved
N and downstream pathway
effectors
F O
Idelalisib
N
HN
N
HN N Capable of inducing
apoptosis and inhibit PI3K
USFDA PI3K-γ and
Duvelisib C H3 AKT phosphorylation signaling [101, 102]
approved PI3K-δ
N and downstream pathway
effectors
Cl O
Duvelisib
Inhibits tumor cell Fibroblast

USFDA differentiation, growth
Erdafitinib FGFR1-4 [103]
approved proliferation, factor
angiogenesis pathway
Table 1: Continued.
Clinical
drugs FDA target
approved
CH3
O O
CH3
CH3
CH3 N
N
N N
H3 C NH
Erdafitinib
O O N Serine/
threonine
H3C CH3 NH USFDA ROCK1/2 Inhibits the enzyme rho
Netarsudil kinase [104]
approved nonreceptor kinase
H2N (AKT)
pathway
Netarsudil
4. Oxidative Stress Associated with HCC 5. Potential of Phytochemicals

Oxidative stress happens once there is an associate degree 5.1. Scavenging of ROS. In any kind of cancer, lethal effects
imbalance between reactive chemical element species due to oxidative stress can be harmful. To counterbalance
(ROS) generation and attenuated by antioxidant enzymes this, antioxidant mechanisms in normal human cells should
or compounds. Excessive production of ROS will cause aero- be needed [129]. Besides, it can be considered as a significant
philous harm to biomacromolecules leading to supermole- process that is taken by phytoconstituents to prevent cancer
cule peroxidation and carcinogenesis [120, 121]. (Table 2).
Anticancer medication increases malondialdehyde The scavenging process is done by different antioxidant
(MDA) level and decreases inhibitor enzymes like GPx, mechanisms so that they could not be able to cause any dis-
GR, CAT, SOD, and GSH [122, 123]. They increase figurement. Some nonradical and radical ions that work as
(MDA) and XO level, cytokines TNF-α, IL-6, i-NOS, cyclo- ROS are hydrogen peroxide (H2O2), superoxide radical
oxygenase-2, and P38-MAPK, NF-κB, and generation of (O2−), hydroxyl radical (.OH), and peroxyl radical (ROO.).
ROS and RNS (reactive nitrogen species) in a viscous cell Protein, DNA, and lipids are excessively harmed due to
[124, 125]. In ethanol, the cytoplasm and mitochondria are these ions and also altered the regular cellular functioning
reborn aldehyde and acetate by vasoconstrictive, ALDH, system. Some phytochemicals act as antioxidant or prooxi-
NAD+, and NADH, which may increase ROS generation dant whose modulators are mainly guided by two factors,
in the liver cell, cause DNA harm, mitochondrial pathology, one is the microenvironment and another is the concentra-
lipid peroxidation, supermolecule denaturation, and stimu- tion of ROS present within the cells. To keep a healthy bal-
late many viscous sicknesses as well as steatosis, fibrosis, cir- anced metabolic activity, the proper quantity of ROS in
rhosis, steatohepatitis, and carcinoma [126]. normal cells is necessary. Now, cells can be damaged
Ordinarily, ROS and RNS are generated by strongly through oxidative stress, especially when ROS comes from
bound enzymes. Too much stimulation of NAD(P) H and extrinsic sources. Normal cells can be injured by external
negatron transport chain results in the production of ROS, factors. In this case, phytoconstituents can play an important
which leads to stress and can injure the cell structures, lipids, role as antioxidants to protect those cells from damage [171].
proteins, and DNA. The production of ROS by vegetative
cells was originally referred to as “the metabolism burst”
because of the redoubled consumption of chemical elements 5.2. Phytochemicals Evaluation in Clinical Trials. Phyto-
by these cells. This method is catalyzed by NAD(P)H chemicals derived from medicinal herbs that are now clini-
enzyme and is important for the disinfectant action of cally tested and used in the treatment of liver fibrosis are
phagocytes [127]. The metabolism of organic compounds Inchin-ko-to (TJ-135), Yi Guan Jian, Fufang-Liu-Yue-Qing,
(L-arginine) forms NO∙ free radicals. The gas synthase and DangguiBuxue Tang [172–175]. An enormous number
(NOS) enzymes are catalyzing the process, and through 5 of anticancer compounds, which are now in progress, never-
electron oxidization of a guanidine gas of L-arginine, it con- theless lead to clinical studies in their initial phases. Through
verts L-arginine into L-citrulline and NO∙ radical [128]. various preclinical researches, the efficacy of different
Table 2: Bioactive compounds and their anticancer effect on hepatocarcinoma.
S. Animal/cell
Phytomolecules Methods Chemical structure Mechanisms Ref.
no. lines
O 1. Liver biochemical
OH
parameters
Andrographolide (labdane Swiss albino In vivo (diethylnitrosamine) 2. Increased MDA and NO
1. [130]
diterpene) mice antioxidant assay O level
3. Decreased level of Gal-3
and IL-6
OH
OH
1. Increased intracellular ROS

O
HCC level
Allicin (organosulfur xenograft 2. Reduced MMP
2. In vivo [131]
compound) tumors in S 3. Activated caspase-3 and
nude mice S PARP

4. Downregulated Bcl-2
1. Significant reduction in cell
OH O OH
viability after treatment
2. Induction of apoptosis in
HepaRG cell line
3. Provoked ROS generation
Aloe emodin
3. HepaRG cells MTT assay, annexin V-FITC/PI 4. Depolarization of MMP [132]
(antraquinone)
OH 5. Induced cell cycle in S-
phase
6. Increases the level of
O mitochondrial cytochrome C,
Fas, p21, Bax/Bcl2, and p53
OH
Liver biochemical parameters

Arbutin (glycosylated
4. Mice In vivo (X-ray irradiation) like ALP, ALT, and AST were [133]
hydroquinone) O O significantly reduced
HO
HO OH
OH
11
Table 2: Continued.
12
S. Animal/cell
no. lines
O N+
Berberine (benzyl- Hep3B, BEL- Cell counting kit-8 assay and EdU It suppressed the glutamine
5. O [134]
isoquinoline alkaloid) 7404 assay uptake by inhibiting SLC1A5
O
OH
1. It induced the apoptosis

O 2. Upregulate the protein
6. Boldine (alkaloid) Wistar rat In vivo (diethylnitrosamine) [135]
expression of Bax and cleaved
caspase 3
HO N
1. Induction of apoptosis
2. Increased the Bax and
NOD/SCID
OH cleaved caspase-3
mice, HepG2, MTT assay, pulmonary metastasis
7. Betulinic acid (triterpene) 3. Decreased the level of Bcl-2 [136]
LM3, model
4. Decreased the level of ROS
MHCC97H
O 5. Inhibit metastasis via
MMP-2, MMP-9, and TIMP2
HO
1. Decreased expression of
SCLC (NCI- MTT assay, BrdU and PCNA O E2F-responsive proliferative
H69, NCI- proliferation assays, CAM assay, genes (cyclin E, thymidylate
Capsaicin (homovanillic
8. H82, DMS53, nude mice models, Chromatin synthase, cdc25A, and cdc6, [137]
acid alkaloid) O OH
DMS114), immunoprecipitation (ChIP) both at mRNA and protein
chicken eggs assay NH levels)
2. G1 phase arrest
Hoechst 33258 staining, MAPK 1. Inhibited the cell
9. Caffeine (purine alkaloid) [138]
activity, flow cytometry proliferation
Table 2: Continued.
S. Animal/cell
no. lines
N 2. Activated the MERK-
regulating kinase and ERK
N pathway
3. Downregulation of EGRF
HepG2, HLF, N
Huh7, PLC/ O
PRF/5
N
OH
HO OH
OH O O
HO OH
1. Antiproliferative
Male albino, HO O 2. Induced proapoptotic body
In vivo (DEN) induced hepato- OH
10. Crocin (apocarotenoid) Wistar rats, 3. Arresting the cell cycle at S [139]
carcinogenesis
HepG2 O HO OH and G2/M phases
OH
4. Induced apoptosis
O O OH
O O
O
O OH
HO
H
N N
N O O
S S
N
H
O O 2. Upregulation of the Bax
Coumarin-6-sulfonamides Sulforhodamine B (SRB) method, 3. Downregulation of the Bcl-
11. HepG2 [140]
(sulfonamide derivative) annexin V–FITC apoptosis assay 2
H
N N 4. Increased caspase-3 levels
N O O
O 5. Arrest in the G2-M phase
S S
O N
H
HO O O
B16F10 cell
Carnosic acid MTT assay, BrdU incorporation 1. Arrested G0/G1 phase
12. xenograft [141]
(polyphenolicditerpene) assay 2. Enhances p21 expression
model
13
Table 2: Continued.
14
S. Animal/cell
no. lines
OH 3. Reduces the values of AST
and ALT
HO
C OOH
O O
1. Inhibited cell proliferation

Liver cancer
Curcumin stem cells
13. MTT assay, Western blot analysis 3. Inhibited the activation of [142]
(diarylheptanoid) (LCCs),
HO OH
the PI3K/AKT/mTOR
HepG2
signaling pathway
OCH3 OCH3
1. Increased expression of
HO O prdx-3
2. Decreased ROS level
3. Upregulation of Bak protein
Daidzein (7- 4. Downregulation of Bcl-2
14. SK-HEP-1 TUNEL assay [143]
hydroxyisoflavones) and BclxL proteins
5. Increased the release of
O mitochondrial cytochrome c
OH 6. Activated the APAF-1,
caspase 9, and caspase 3
O
Male Swiss OH
1. Decreased incidence of
mice, Wistar preneoplastic foci
In vivo (N-nitrosodiethylamine,
15. Embelin (benzoquinone) albino rats, 2. Decreased biochemical [144]
CCl4)
Sprague HO
markers (SGOT, SGPT, ALP,
Dawley rats GGT, GST, and LPO)
O
1. Inhibited proliferation of
C57BL/6J
Esculetin (coumarin HCC cells
16. mice In vivo MTT assay [145]
derivative) 2. Arrest cell cycle at S phase
Hepa1-6 cells
Table 2: Continued.
S. Animal/cell
no. lines
OH 4.Increased caspase-3 and
caspase-9 activity
5. Increased Bax expression
6. Decreased Bcl-2 expression
O O OH
OH O OH
1. Attenuated cholesterol
HepG2 Western blotting, quantitative
synthesis and oncogenic AKT
Hep3B real-time PCR, tumor xenograft
signaling
17. Emodin (anthraquinone) Huh7 assay, Ki67 cell proliferation assay, [146]
2. Inactivated STAT3
SK-HEP-1 annexin-V staining, luciferase

H3 C OH
3. Cell cycle arrest in the G1
PLC/PRF5 assay
phase
O
OH O OH 1. Inhibited HCC cell

proliferation and migration
BALB/c nu/nu
Emodinsuccinylester O 2. Decreased transcription
athymic nude Western blot, quantitative RT-
18. (trihydroxyanthraquinone level and protein expression of [147]
mice, Hep3B, PCR, xenograft mouse model OH
derivative) H3C O
androgen receptor
Huh7
3. Enhanced of zeste homolog
O O 2
OH
OH
HO O 1. Inhibited Hep3B cells by

Mice, Hep3B, OH both antiproliferation and
He-pG2, SK- Western blot analysis, cell viability proapoptosis
(-)-Epigallocatechin-3-
19. hep1, HCC- analysis, tumor xenograft in nude O 2. ERα36-EGFR-Her-2 [148]
gallate (catechin)
LM3, Huh7, mice model feedback loop, PI3K/Akt, and
OH OH
SMMC7721 MAPK/ERK pathways were
O
inhibited
OH
OH
1. Inhibited the growth of

Hepa1-6 cell Cell viability assay, Flow
20. Genistein (isoflavone) Hepa1-6 cells [149]
line cytometry
15
Table 2: Continued.
16
S. Animal/cell
no. lines
HO O
OH O
OH
HO
1. Decreased the size of
O tumors
Wistar albino HO
2. Decreased the levels of
21. Gallic acid (phenolic acid) In vivo (diethylnitrosamine) [150]
rats marker enzymes in serum
OH 3. Decreased the levels of
AgNORs and PCNA
HO
OH
H
O
18?-Glycyrrhetinic acid Decreased cell viability in
22. HepG2, H22 MTT assay [151]
(triterpene) higher concentration
HO
1. Induced cell death

2. Activated mitogen-activated
3. Protein kinase ERK1/2
23. Hesperidin (flavonoid) HepG2 cells MTT assay, DAPI staining [152]
5. Arrested G1 phase cells
6. Induced proptosis like cell
death
7. Induced depletion of MMP
Table 2: Continued.
S. Animal/cell
no. lines
OH
HO OH
OH
HO
O O CH3
O O
HO CH3
O O
OH
OH O
HO
2. Arrested G0/G1 cell cycle
CCA cell lines phase
HO
Honokiol (biphenol (KKU-100 3. Induced apoptosis
24. MTT assay [153]
neolignans) and KKU- 4. Suppressed the adhesion
213) and migration of cell
5. Inhibited the MMP-9 and
MMP-2 activity
OH
HO O
OH 1. Inhibited cell proliferation,

O migration, and invasion
O
2. Induced cell apoptosis
Cell counting kit-8 assay, BrdU OH O O OH 3. Reduce the expression of
incorporation assay, Guava Nexin O
25. Kaempferol (Flavonoid) HepG2 cell OH miR-21 [154]
assay, two-chamber migration
4. Enhanced the expression of
(invasion) assay OH
PTEN
O O OH 5. Inactivated PI3K/AKT/
mTOR signaling pathway
HO OH
OH
MHCC-LM3, 1. Inhibited in vivo

26. Lupeol (triterpene) MTT assay, xenograft model [155]
nude mice tumorigenicity
17
Table 2: Continued.
18
S. Animal/cell
no. lines
(BALB/c-nu/ 2. Downregulated CD133
nu) expression
3. Sensitize (PTEN)-Akt-
ABCG2 pathway
H
H
HO
H
OH HO 1. Inhibited the proliferation,

migration, and invasion of
cells
HepG2 cells, 2. Induced apoptosis
MTT assay, Transwell assays, flow
27. Magnolol (lignan) nude mice 3. Induction of ER stress [156]
cytometric analysis
(Balb/c nu/nu) 4. Release of cytochrome C
5. Arrested S-phase
6. Suppressed tumor growth
in vivo
OH
1. Decreased ROS formation

OH O
2. Restored the MMP
O
3. Regulation of Bcl-2/Bax
Mangiferin (xanthone Male Swiss
28. In vivo (lead-induced) MTT assay OH OH 4. Inhibited activation of [157]
glucoside) albino mice
MAPKs (phospho-ERK 1/2,
HO phosphor-JNK phospho- p38)
OH
O OH
HO
1. Inhibited the cell

proliferation
2. G0/G1 and G2/M phase
Naringenin Flow cytometry arrest
29. HepG2 cells [158]
(trihydroxyflavanone) Cell viability assay 3. Induced apoptosis
4. Increased ratio of Bax/Bcl-2
5. Release of cytochrome C
6. Activation of Caspase 3
Table 2: Continued.
S. Animal/cell
no. lines
OH
HO O
OH O
OH
OH
1. Suppressed expression of
activated AKT
Cell counting kit 8, flow
Oleuropein 2. Inhibited cell growth
30. HepG2, Huh7 cytometric analysis, cell viability O [159]
(monoterpenoid) O
assay, luciferase assay
4. Inhibited PI3K/AKT
H
O O
signaling pathway
HO
O O
HO OH
OH O
OH 1. Induced cytotoxic effect

Oleanolic acid MTT assay, cell viability assay,
31. HepG2 2. G0/G1 cell cycle arrest [160]
(triterpenoid) annexin V-FITC
3. Reduced MMP
O
H
HO
H
Parthenolide MTT assay, DAPI, TUNEL 1. Increased the number of

32. HepG2 [161]
(sesquiterpene lactone) staining, Western blotting, apoptotic nuclei
19
Table 2: Continued.
20
S. Animal/cell
no. lines
monodansylcadaverine (MDC), 2. Reduced expression of Bcl-2
AO staining 3. Increased expression of Bax,
H p53, and caspase-3 and 9
4. Induced autophagy
5. Inhibited the expression of
O the Ki-67 gene
O
H3C
2. Regulated the NF-kB
H3C
H
signaling of NSCLC cells
NSCLC N H
N N 3. Significantly reduced the
(A549, NCI- O
Phycocyanin MTT assay, annexin V-FITC and O expression of MMP-2 and
33. H1299, NCI- N [162]
(phycobiliproteins) 7AAD staining H MMP-9
H460, and H3C CH3
CH3 4. Suppressed the proliferation
H3C
LTEP-A2)
of NSCLC cells
COOH COOH
5. Arrested G1 and S phase of
cell cycle
OH
OH 1. Suppressed cell viability

3. Inhibited the activation of
HCC (LM3), HO O
Flow cytometry, TUNEL assay, the JAK2/STAT3 pathway
34. Quercetin (flavonoid) nude mice [163]
qRT-PCR, Western blotting 4. Inhibited cell migration and
model
invasion
5. Inhibited tumor growth in
OH nude mice model
OH O
Diamino-benzoic acid and 1. Decreased ROS and MDA

bromodeoxyuridine assays, lactate concentration
HepG2 cell dehydrogenase leakage assay, 2. Arrested cell growth at
35. Rutin (flavonoid) [164]
line fluorimetric assay, higher concentration
dichlorofluorescein assay, 3. No cytotoxic effect on
northern blot HepG2 cells
Table 2: Continued.
S. Animal/cell
no. lines
OH
HO
HO
HO OH
O
O
HO
O
HO OH
O
OH O
HO
OH
HO O
O
O 1. Decreased p65
phosphorylation
Rosmarinic acid (coumaric H22 tumor- ELISA, Western blotting, qRT-
36. 2. Inhibited the tumor growth [165]
acid derivative) bearing mice PCR HO
3. Decreased the elevated level
OH of cytokines
OH
OH
OH
2. Arrested G1 phase
MTT assay, flow cytometric 3. Downregulated the
37. Resveratrol (polyphenol) HepG2 analysis, Western blot analysis, expression of cyclin D1, p38 [166]
laser confocal microscopy MAP kinase, Akt, and Pak1
HO
4. Increased ERK activity
OH 5. Induced apoptosis
Human 1. Inhibited cell proliferation

Salidroside (p-hydroxy- hepatocellular MTT assay, Western 2. Arrested G2 phase
38. [167]
phen-ethyl-β-d-glucoside) carcinoma immunoblotting 3. Inhibited CDK-cyclin
(HHCC) activity
21
Table 2: Continued.
22
S. Animal/cell
no. lines
OH
OH
HO OH
OH
1. Enhanced the expression of

PARP and Caspase3
2. Increased the sub-G1
Cytotoxicity assay, ethidium H population
homodimer assay, 3. Attenuated the expression
Ursolic acid HepG2, deoxynucleotidyl transferase- OH of AEG1gene
39. [168]
(pentacyclictriterpenoid) Hep3B mediated dUTP nick-end labeling 4. Increased the
assay, cell cycle analysis, Western O
phosphorylation of AMPK,
blotting H GSK3β, and coenzyme A
5. Attenuated the
HO phosphorylation of AKT and
mTOR
1. Inhibited the tumor growth
2. Decreased intrahepatic
Nude mice metastasis
Xenogen in vivo imaging system,
Withaferin A (steroidal model, 3. Inhibited the expression of
40. Western blot analysis, liquefied [169]
lactone) MHCC97, Pyk2, ROCK1 protein, and
Matrigel assay
JHH-5 VEGF
4. Suppressed the formation of
actin projection
Table 2: Continued.
S. Animal/cell
no. lines
OH
H
O O
H
O
H
H H
O
OH
H
MTT assay, cell viability assay,
1. Reduced cell viability
flow cytometry, annexin-V/PI
HepG2, Bel- 2. Arrested S phase cell cycle
Xanthatin (sesquiterpene double staining assay, Western
41. 7402, SMMC- O O 3. Induced apoptosis [170]
lactone) blotting, immunofluorescence
7721 4. Induced ERS and activated
staining, dual-luciferase reporter O UPR pathway
gene assay
H
23
phytochemicals has represented such as, andrographolide, Table 3: Medicinal plants and their bioactive compounds used in
berberine, capsaicin, curcumin, genistein, ursolic acid, and radiotherapy and chemotherapy.
withaferin A.
Andrographolide restrains tumor development by Plants as radioprotector/radiosensitizer in HCC
obstructing tumor adjustment to hypoxic conditions. The Decreases the depleted level of endogenic
Amaranthus
detected effects of andrographolide (100 mg/kg) were attrib- antioxidant enzymes during radiotherapy
paniculatus Linn.
of mice liver.
uted to the restriction of the hypoxia-inducible figure (HIF)
[176]. The recovery rate of different myeloma patients has Coronopus didymus Enhance the level of antioxidant enzymes
made strides through the use of andrographolide in a clinical (L.) in the liver of mice.
trial [177, 178]. While investigations are undertaken via the Augmented the SOD, CAT, and GSH
Grewia asiatica L.
large quantity of information on preclinical efficacy, clinical levels in the liver of irradiated mice.
studies are limited in the evaluation of berberines and It protected plasmid DNA and reduced
andrographolide genuine potential as a carcinoma opera- Glycyrrhiza glabra L. the liver microsomal LPO level in rat from
tor [179]. irradiation.
Capsaicin supplementation significantly reduced the In vitro and in vivo studies show the
Hypericum
establishment of preneoplastic foci in a rat model of hepato- increased level of SOD, CAT, GSH-Px,
perforatum L.
carcinogenesis caused by diethylnitrosamine, HCC cell lines and GSH during radiation therapy
were likewise stopped from proliferating, and apoptosis was Pilea microphylla (L.) Increased level of endogenous antioxidant
triggered on a dose-based manner [180, 181]. Furthermore, Liebm. enzyme levels in the liver of mice.
HCC cells were shown to be more sensitive than normal Augmented the SOD, CAT, and GSH
Rosmarinus officinalis
hepatocytes to capsaicin induced cytotoxicity suggesting that levels in blood and liver of mice during
L.
it might have a chemotherapeutic effect [182]. the radiation therapy.
Curcumin is a chemopreventive agent with a lot of opti- Xylopia aethiopica
Protect the liver of rat from γ-radiation
mism. This has prompted clinical practices to investigate the (Dunal) A.Rich.
pharmacokinetics and effectiveness of curcumin in patients. Bioactive phytomolecules as adjunct with chemotherapy
It was shown to be safe and nontoxic in phase I clinical stud- Used as an adjuvant with vinorelbine
ies, even at large dosages (8 g/day). However, it had limited Curcumin chemotherapy and enhances the
absorption individuals [183, 184]. Their clinical trials, either antiproliferative effect of drugs.
alone or as anticancer agent combinations, demonstrated Used as an adjunct in doxorubicin,
efficacy, despite challenges to bioavailability, in several dis- busulfan, and cisplatin chemotherapy. It
ease sites [185–187]. Quercetin also increased cytotoxic effects of these
The medication with genistein (140 mg/kg) is by pre- drugs and protect from drug-induced
venting aberrant nuclear β-catenin harvests and concealing nephrotoxicity.
WNT signaling features [188]. Ursolic acid (UA) was rep- Used as an adjunct with cisplatin and 5-
resented to upgrade the restorative impacts of oxaliplatin Ginsenosides FU chemotherapy and enhanced
in the mouse model of CRC by restraining the tumor antiproliferative effect.
and expanding the survival rate. Tumor shape is lessened
by the UA nanoparticles by focusing on caspases and
p53 with downregulation of Bcl-2 and cIAP, instigating 5.4. Modification of Genomic Stability. Phytochemicals tar-
apoptosis and driving to cervical cancer cell distortion gets both DNA repair and their damage mechanism, where
[189], whereas the tumor development of human colorec- genomic stability within cells plays an important role.
tal carcinoma (HCT-116) cells which overexpress AKT Besides, this genomic stability also helps a lot when chemo-
and microvessel arrangement is hindered through the ver- preventive agents trigger a selective number of cancer cells
bal organization of Withaferin A (5 mg/kg) in a mouse [194, 195]. There are some therapeutic agents which gener-
model [190]. ate the DNA repair pathways in normal cells to modulate
the stress conditions within the cells. In a contradicting
5.3. Detoxification of Enzymes. Xenobiotic compounds are way, DNA damage response can also be increased when can-
responsible for putting impacts on humans affecting tis- cer cells are exposed in a large number. As a result, apoptosis
sues. To lessen that impact, there are several responses can happen, and cells can be dead permanently [196].
or potentials [191]. Among them, the initialization of
some detoxifying enzymes is important, especially for the 5.5. Cancer Cell Metabolism. Cell metabolism in tumors
liver [192]. Detoxified enzymes can be induced by antiox- plays an important role in the stimulation process in proto-
idative phytochemicals found in plants. These phytochem- oncogenes by involving ROS production [197, 198]. The sur-
icals mainly target antioxidant response or electrophile vival and growth rate of tumor cells largely depend on their
response elements (ARE/EpRE) to modulate the molecular metabolic requirements which are adjusted by themselves
pathways. These pathways mainly depend on three main [199]. Energy requirements are supplied by glucose, and
components like ARE, nuclear factor erythroid 2 p45- thus, it initiates tumor growth. Besides glucose, glutamine
related factors 2 (Nrf2), and Kelchlike ECH-associated also plays an important role in tumor growth by providing
protein 1 (Keap1) [193]. nitrogen for the biosynthesis process. Phytochemicals can
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Hindawi

Oxidative Medicine and Cellular Longevity

Correspondence should be addressed to Pracheta Janmeda; [email protected],

Received 4 August 2021; Accepted 6 October 2021; Published 31 October 2021

Academic Editor: ChongDe Sun

1. Introduction ily are VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF,

Cell proliferation Vascular permeability

RTKs ﬁlm to LPR-5, and the β-catenin demolition complex is

mycin analog (rapalog) mTOR inhibitor administered per

2.5. Fibroblast Growth Factor Pathway. Fibroblast growth

2.6. Enzyme (P450) Reactions Generating ROS in Liver

Figure 5: Generation of reactive oxygen species (ROS).

Role of CYPs in ROS mediated diseases

Reactive –Protein modification

Oxidative stress Apoptotic Autophagic

Figure 8: Signaling pathways regulating mitochondrial function.

complex stimulates the CAMKIV and AMPK that leads to STA

Inhibits tumor cell Fibroblast

4. Oxidative Stress Associated with HCC 5. Potential of Phytochemicals

1. Increased intracellular ROS

nude mice S PARP

Liver biochemical parameters

1. It induced the apoptosis

1. Inhibited cell proliferation

SK-HEP-1 annexin-V staining, luciferase

OH O OH 1. Inhibited HCC cell

HO O 1. Inhibited Hep3B cells by

1. Inhibited the growth of

1. Induced cell death

OH 1. Inhibited cell proliferation,

MHCC-LM3, 1. Inhibited in vivo

OH HO 1. Inhibited the proliferation,

1. Decreased ROS formation

1. Inhibited the cell

OH 1. Induced cytotoxic eﬀect

Parthenolide MTT assay, DAPI, TUNEL 1. Increased the number of

OH 1. Suppressed cell viability

Diamino-benzoic acid and 1. Decreased ROS and MDA

Human 1. Inhibited cell proliferation

1. Enhanced the expression of

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