Medicine in Drug Discovery 17 (2023) 100147

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Medicine in Drug Discovery

journal homepage: www.elsevier.com/locate/medid

A review of the pharmacodynamic effect of chemo-herbal drug combinations

therapy for cancer treatment
Ambrose Okem a,⇑, Charlotte Henstra b,d, Maarten Lambert c, Rose Hayeshi d
a
Department of Anaesthesia, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
b
Department of Pharmaceutical Technology and Biopharmacy, Faculty of Science and Engineering, University of Groningen, the Netherlands
c
Department of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Science and Engineering, University of Groningen, the Netherlands
d
DSI/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, South Africa

A R T I C L E I N F O A B S T R A C T

Keywords: There is mounting evidence that cancer patients co‐administer herbal drugs with chemotherapy, however,
Herbal‐drug information on the pharmacodynamic (PD) effects of such combination therapy is scarce. Natural products
Herbal medicine including crude extracts, herbal formulas, and bioactive compounds from plants hold great potential to prevent
Pharmacodynamics and treat cancers. More importantly, some herbal drugs can reduce the incidence of chemotherapy‐induced
Synergistic
toxicity including oral mucositis, gastrointestinal toxicity, hepatotoxicity etc. This review focuses on the effec-
Combination therapy
tiveness of some herbal products as adjuvant therapy and describes the possible mechanisms of chemo‐herbal
drug PD interactions in enhancing the efficacy/ or reducing the side effects of chemotherapy. We also high-
lighted recent advances in preclinical in vitro and in vivo studies to establish the effectiveness of herbal medicine
to enhance efficacy or counteract chemotherapy‐induced side effects. In addition, we draw particular attention
to the synergistic effects of chemo‐herbal drug combination therapy to prevent and treat cancers using evi-
dence from clinical trials. We concluded that herbal drugs hold great potential as adjuvant therapy for the pre-
vention and treatment of chemotherapy‐induced side effects. It is important to also highlight that the clinical
evidence on chemo‐herbal drug combination therapy is limited. There is an urgent need for an in‐depth PD
evaluation including the safety pharmacology of chemo‐herbal drug combination therapy as well as reliable
evidence from multicentre clinical trials to establish the beneficial or negative effects of chemo‐herbal drug
combination therapy in the ongoing fight against cancer.

1. Introduction can lead to drug resistance [2]. Evidence has shown that cancer
patients use herbal medicines/ products also often referred to as com-
Cancer is a complex disease and requires a multifaceted treatment plementary or alternative medicine (CAM) in combination with
approaches. Systemic therapies using FDA‐approved drugs remain the chemotherapy. Some of the reasons why most cancer patients opt to
mainstream treatment approaches for metastatic cancers. One of the use herbal medicine in combination with chemotherapy include reliev-
main disadvantages of chemotherapy is that treatment in most cases ing the side effects of chemotherapy, while others believe that herbal
comes with severe side effects. As most chemotherapeutic drugs target medicine has several health benefits such as promoting overall health,
the DNA of cells, the side effects of the therapy are often caused by managing disease symptoms, and improving the function of the
damage to rapidly dividing cells such as the bone marrow, hair folli- immune system [3]. Apart from this voluntary use of herbal products
cles, and the (sub) mucosa of the GI tract [1]. Severe side effects can by patients, there is also research into the possibility of including her-
lead to a decrease in the quality of life of patients thereby resulting bal medicines as part of cancer treatment, for the reduction of
in non‐compliance by patients in taking their chemotherapy, and this chemotherapeutic side effects [4].

Abbreviations: CAM, Complementary or alternative medicine; DDR, DNA damage response; EGCG, Epigallocatechin gallate; ERK1/2, Extracellular signal‐regulated kinase; IL‐6,
Interleukin 6; MDR, Multidrug resistance; NF‐κB, Nuclear factor‐κB; P‐gp, Permeability glycoprotein; PD, Pharmacodynamics; PD‐L1, Programmed death ligand‐1; PK,
Pharmacokinetics; Rg3, Red ginseng 3; ROS, Reactive oxygen species; STAT‐3, Signal transducer and activator of transcription 3; xIAP, X‐linked inhibitor of apoptosis protein.
⇑ Corresponding author.
E-mail address: [email protected] (A. Okem).

https://doi.org/10.1016/j.medidd.2022.100147
Received 5 September 2022; Revised 7 November 2022; Accepted 14 November 2022
Available online 24 November 2022
2590-0986/© 2022 The Author(s). Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Okem et al. Medicine in Drug Discovery 17 (2023) 100147

The concomitant use of herbal medicine with cancer therapy can Epigallocatechin gallate (EGCG) from Camellia sinensis extract
either lead to pharmacokinetic (PK) or pharmacodynamic (PD) inter- enhanced the cytotoxicity of 5‐fluorouracil in resistant colorectal can-
actions. In contrast to the mounting evidence on the PK interaction cer cells [14]. EGCG enhanced 5‐fluorouracil‐induced cytotoxicity and
of chemo‐herbal drug combination therapy, there is a paucity of infor- inhibited metastasis of the 5‐fluorouracil‐resistant cells by facilitating
mation on the PD interaction of herbal medicine with anticancer apoptosis and restricting the cell cycle. EGCG also suppressed Notch1,
drugs. Pharmacodynamic interactions arise when one drug alters the Bmi1, Suz12, and Ezh2, and upregulated self‐renewing suppressive‐
pharmacological effect of another drug in a combination regimen miRNAs, miR‐34a, miR‐145, and miR‐200c, which are some of the
[5]. These interactions can either be synergistic/additive or antagonis- main pathways targeted in 5‐fluorouracil therapy. In vivo experiments
tic. Synergistic interactions occur when two or more drugs (or herbs) in the same study confirmed these results, where EGCG therapy inhib-
enhance a pharmacological effect which is greater than the sum of ited tumour development in a xenograft mouse model.
the individual effects of each drug. The enhancement of efficacy allows Gemcitabine is the first‐line therapy for metastatic pancreatic can-
for decreasing the dose of the chemotherapeutic, leading to reduced cer which is one of the deadliest malignancies. However, gemcitabine
incidence of toxicity and resistance [6]. Antagonistic (or opposing) has little impact on median overall survival for patients with meta-
interactions occur when two or more drugs (or herbs) with opposite static disease [15]. Yu & Chen [16] investigated the synergistic effect
pharmacological activities are administered concurrently. These activ- of Rauwolfia vomitoria extract and gemcitabine for treating pancreatic
ities can either be on a receptor, or a receptor signalling pathway [7]. cancer. The addition of R. vomitoria extracts to gemcitabine signifi-
Although PD interactions may not be as frequently reported or cantly inhibited cell growth with a dose reduction effect for gemc-
straightforward as PK interactions, they are a significant factor to con- itabine. The authors also found that the combination treatment
sider, especially when prescribing drugs or establishing guidelines for significantly suppressed tumour growth and metastases in an ortho-
the concurrent use of herbal medicine with chemotherapy. topic pancreatic cancer mouse model. R. vomitoria extract reinforces
This review aimed to critically review the recent evidence of gemcitabine‐induced apoptosis by cleavage of caspase‐3 and −8
chemo‐herbal drug PD interactions, highlighting the positive synergis- [17]. Caspase‐3 cleaves cytoskeletal and nuclear proteins that play a
tic effects of chemo‐herbal drug combination therapy to treat cancers. role in maintaining DNA integrity.
The review also draws particular attention to the effectiveness of her- Resveratrol is a renowned bioactive compound synthesized by over
bal medicine in reducing chemotherapy‐induced side effects, high- 70 plant species [18]. Resveratrol possesses numerous biological activ-
lighting some recent evidence from clinical trials on the concomitant ities, but the best‐known capacity of resveratrol is to act as a potent
use of herbal medicine with chemotherapeutics. antioxidant [19,20]. Resveratrol, in combination with clofarabine
and 5‐fluorouracil, showed prominent synergistic interactions. For
instance, the combination of resveratrol and clofarabine resulted in
2. Preclinical research demonstrating the synergistic effects of significant inhibitory effects on malignant mesothelioma growth
herbal medicine co-administer with chemotherapeutics [21]. In the study, the authors demonstrated that adjuvant therapy
with resveratrol inhibited cell proliferation and had limited toxicity
Complementary and alternative medicine (CAM) exhibit chemopre- on healthy mesothelial cells. The study also indicated that the synergy
ventive effects by inhibiting tumour initiation, cell growth, metastasis, was associated with the inhibition of Specificity protein 1 (Sp1) and
or a combination of these stages. Emerging preclinical evidence has several Sp1‐regulated gene products. The Sp1 protein is a nuclear tran-
shown that combining CAM with standard chemotherapy can improve scription factor involved in the expression of various housekeeping
treatment outcomes and enhance other health benefits with minimal genes and is frequently upregulated in cancer cells [21]. Inhibition
incidence of toxicity (Table 1). of this protein often suppresses tumour formation, metastasis and
growth.
Preclinical evidence has shown that combining quercetin and cis-
2.1. Herbal medicine exhibiting synergy with chemotherapy platin produced a synergistic effect in malignant mesothelioma cells,
the combination therapy inhibited cell proliferation more than cis-
Resistance to platinum‐based chemotherapy is one of the major platin alone [22]. The authors reported a significant increase in
hurdles in the treatment of various human cancers. A study by Yallapu caspase‐3 and‐9 when treated with quercetin which could be the rea-
et al. [8] found significant synergism when a cisplatin‐resistant ovar- son for the synergistic interaction between quercetin and cisplatin
ian cancer cell line was treated with curcumin. The authors pre‐ since cisplatin also induces caspases‐3 and −9 [22]. Co‐treatment of
treated the cells with curcumin to induce chemosensitization then fol- astrocytoma cells with temozolomide and quercetin was reported to
lowed by the platinum drug treatment 2 h later. In another study, Park initiate programmed cell death more effectively than the individual
et al. [9] found that co‐treatment with curcumin and cisplatin resulted temozolomide treatment [23]. The authors also reported significant
in a greater synergistic effect by activation of caspase‐3 and upregula- apoptosis which was correlated with an increase in caspase‐3
tion of phosphor‐mitogen‐activated protein kinase and phosphor‐ expression.
extracellular signal‐regulated kinase1/2 signalling in bladder cancer Ursolic acid is an ubiquitous bioactive compound in several medic-
cell lines. Emerging evidence has shown that curcumin exerts numer- inal plants, and it is known to suppress various inflammatory and pro‐
ous biological effects by targeting several molecular and cellular path- inflammatory signalling cascades [24]. Shan et al. [25] reported that
ways such as cell death, p53, Akt, mitogen‐activating protein kinases ursolic acid synergistically enhanced the therapeutic outcome of oxali-
(MAPK), microRNAs, and PTEN [10–12]. In a study by Banerjee platin in colorectal cancer in both in vitro and in vivo models. The
et al. [13] the authors found that the combined treatment of docetaxel observed synergistic activity reported in the study was associated with
(10 nM) and curcumin (20 μM) for 48 h significantly inhibited the pro- the ability of ursolic acid to inhibit multiple kinase pathways including
liferation and induced apoptosis in prostate cancer (PC‐3) (DU145 and MAPK, P13K/AKT and NF‐κB signalling pathways. A similar synergis-
PC3) cells via modulation of COX‐2, p53, NF‐κB, phospho‐Akt, PI3K, tic effect was observed when ursolic acid and cisplatin were co‐
and receptor tyrosine kinase (RTK). These molecular targets play piv- administered to cervical cancer cells. In the study, the authors reported
otal roles in cancer pathogenesis, hence, the ability of curcumin to that the combination treatment enhanced apoptosis and inhibited cell
interfere with such pathways in combination with conventional proliferation via suppression of NF‐ κB p65 [26].
chemotherapy may provide an alternative treatment option for cancer Triptolide from Tripterygium wilfordii has been reported for sensitiz-
patients by enhancing therapeutic outcomes and reducing drug ing breast cancer cells to doxorubicin through increased DNA damage
resistance. [27]. The study showed that after 3 h of triptolide exposure, breast

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Table 1
Preclinical evidence of herbal medicine attenuates chemotherapy-induced side effects and exerts synergistic activity.

Herbal product Chemotherapy Malignancy Mechanisms of action Cell line/ animal model Reference

Scutellaria baicalensis Georgi Cisplatin Lewis lung Induced apoptosis and Inhibited tumour growth LLC Cell line and C57BL/6J [56]
carcinoma (LLC) both in vitro and in vivo. Also, attenuates mouse model
chemotherapy-induced cachexia and acute kidney
injury in a mouse model.
23-Hydroxybetulinic acid from Doxorubicin Multiple cancer cell Improve the sensitivity of the tumour cells to Cell line and ICR mice [57]
Pulsatilla chinensis (Bunge) lines doxorubicin through increasing intra-tumour bearing sarcoma 180
Regel doxorubicin concentration and inhibiting carcinoma tumours
doxorubicin-induced up-regulation of P-gp in the
tumour.
Moringa oleifera 5-fluorouracil, Hepatocarcinoma Suppressed hepatocarcinoma sarcoma and Mouse model [58]
Cyclophosphamide sarcoma improved body weight.
Morinda citrifolia Cisplatin NIH-3 T3 cells Exhibited cytoprotective effects against normal NIH-3 T3 cell line [59]
sensitive to sarcoma cells and attenuated cardiac injury in a mouse
virus and leukaemia model.
virus propagation
Huang-Lian-Jie-Du-Tang Cinnamaldehyde Human hepatoma Induce mitochondria-medicated and death Hep G2 cell line [60]
cells receptor-mediated apoptosis.
Salvia miltiorrhiza Bunge Oxaliplatin glioblastoma Relieve acute chemotherapy-induced neuropathic Mouse model [61]
pain.
Shenmai injection (Red ginseng Adriamycin, Colorectal carcinoma Enhance efficacy by increasing the plasma Colon cancer xenograft [62,63]
and Radix ophiopogonis) Paclitaxel and 5- concentration of chemotherapy. models
fluorouracil
BP10A herbal formular Oxaliplatin and Colon carcinoma Significantly decrease tumour growth by inhibiting Patients-derived xenograft [64]
(Descurainiae sophia and irinotecan the Ki-67 expression for tumour cell proliferation model
Peucedani praeruptorum) and CD31 for angiogenesis.
Gegen Qinlian decoction (Radix Irinotecan Colorectal carcinoma Ameliorate gut toxicity induced by chemotherapy, HT-29 colon cancer cells [65]
Puerariae, Radix and significantly inhibit tumour growth by xenograft
Scutellariae, Coptis chinensis decreasing the levels of pro-inflammatory
and Radix Glycyrrhizae cytokines.
Praeparata)
Polyoxypregnanes (Marsdenia Paclitaxel Colon and breast Restored chemosensitivity in ABCB1- SW620, HEK293, MDA435/ [66]
tenacissima) cancers overexpressing cancer cells via inhibition of ABCB1 LCC6 and MDA435/LCC6
efflux activity. MDR1 cell lines and
xenograft models
Marsdeniae tenacissimae Paclitaxel and Leukaemia and lung Sensitive various cell lines to chemotherapies H460 and H197 (lung), KB- [67,68]
gefitinib cancer significantly inhibited tumour growth in mouse 3–1, HeLa, HepG2 and K562
models. (leukaemia) cell lines and
xenograft mouse models.
Calycosin and Formononetin Temozolomide Brain Inhibited proliferation and migration of glioma Glioma cell line and [69]
(Astragalina alpestris) cells and promote apoptosis by upregulating xenograft
caspase-3 and-9.
Propolis 5-fluorouracil Colorectal carcinoma Reduced aberrant crypt foci (ACF) were counted Mouse xenograft [70]
and the pathological lesions in the distal colonic
epithelial tissue. It also reduced the expression of
Cox-2, iNOS, and β-catenin proteins.
Resveratrol Temozolomide Brain Induced apoptotic cell death and cytoprotective Cell line and xenograft mouse [71]
autophagy through ROS burst and extracellular models
signal-regulated kinase.
Curcumin Paclitaxel Breast Increased drug accumulation in tumour cells and Xenograft mouse model [72]
decreased tumour growth.
Xanthorrhizol Tamoxifen Breast Significantly decreased tumour volume by MCF-7 xenograft mouse [73]
increasing protein expression of P38 and P27. model
Sijunzi decoction (Panax ginseng Cisplatin Lung Attenuated cisplatin-induced toxicity, increased Xenograft mouse model [74]
and Glycyrrhiza uralensis) the levels of myogenic proteins such as myosin
heavy chain and myogenin and decreased
atrogin-1.
Quercetin Cisplatin Oral Promotes cisplatin-induced apoptosis by inhibiting Tca-8113 and SCC-15 cell [75]
the phosphorylation Akt and IKKβ thereby lines
suppressing the NF-κB and anti-apoptotic protein
xIAP.
Orange peel extract Doxorubicin Oesophagal cancer Orange peel extract intervention protects against XTT xenograft model [76]
cellular toxicity of doxorubicin in vitro by
decreasing cellular apoptosis of ESCC CSCs genes.
In vivo model revealed that the orange peel extract
intervention significantly reduced the tumour size,
systemic toxicity, and oxidative stress.
Shengbai decoction Cyclophosphamide Melanoma Significantly alleviated histopathological damage, B16F10 tumour-bearing [77]
and reduced tumour growth and the mouse model
concentrations of IL-6, IFN-γ and TNF-α in serum.
The combination treatment also enhanced the
expression of NF-κB and promoted apoptosis
compared with Cyclophosphamide alone.
QHF formula (Cinobufotalin, Cisplatin Hepatocellula Significantly enhance apoptosis, increased the H22 cell mouse model [78]
Ginsanoside Rg3, carcinoma proportion of cells in the G0/G1 phase and

(continued on next page)

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Table 1 (continued)
Herbal product Chemotherapy Malignancy Mechanisms of action Cell line/ animal model Reference

Notoginseng and lentinan) decreased the cell proportion in the S-phase. QHF
intervention significantly inhibited the growth of
tumours and prolong the survival time of mice.

cancer cells had an increased sensitivity to doxorubicin. Triptolide The combination of 5‐fluorouracil and resveratrol interfered with
enhanced the sensitivity of breast cancer cells to doxorubicin, com- the phosphorylation of signal transducer and activator of transcription
pared to other chemotherapeutics such as 5‐fluorouracil, paclitaxel 3 (STAT3) and Akt in human colorectal cancer cells [33]. The dephos-
and mitomycin C. Interestingly, triptolide hindered the DNA damage phorylation caused less binding to the transcriptionally regulating
response (DDR) to DNA double‐strand breaks. The DDR consists of sev- telomerase reverse transcriptase (hTERT) promoter. Consequently,
eral cellular pathways that detect, activate and repair DNA damage. the lack of binding reduced telomerase activity, which is crucial to
The DDR is essential for the protection of the integrity of the genome maintaining chromosomal stability over repeated cell division. An
and for ensuring genomic stability [28]. Defects in the DDR raise the additional action of the combination of 5‐fluorouracil with resveratrol
risk of gene mutation, chromosome abbreviation and genome instabil- is the inhibition of Akt phosphorylation. Akt is a serine/threonine
ity in human tissues and cells and are known to be a crucial factor in kinase which plays a crucial role in cell proliferation, migration and
the initiation of tumorigenesis. An improved DDR, however, is gener- survival.
ally associated with cancer chemotherapy resistance. Thus, by hinder- Elucidating the molecular mechanisms of chemo‐herbal drug com-
ing the DDR using triptolide, the breast cancer cells were not able to bination therapy has been the major bottleneck hampering the under-
restore the DNA damage caused by chemotherapeutics [28]. standing of the synergy and attenuation of chemotherapy‐induced side
effects in the clinical use of CAM [34]. Recently, Wu et al. [35] estab-
lished the molecular mechanisms by which the combination of Xiaoji
decoction (XJD) and cisplatin exert a high magnitude of apoptosis in
2.2. Herbal medicine exhibiting cell cycle arrest non‐small cell lung cancer cells both in vitro and in vivo. The authors
revealed that XJD decoction decreased the IncRNA PVT1 and
Cell cycle arrest is an important mechanism in which cells can increased the miR1h1a‐sp expressions which were the major factors
physically be halted from progression through the normal cell cycle responsible for the synergy and attenuative effects of this combination
by a chemical agent [29]. One such chemical agent is ginseng, a pop- therapy. More research on the most frequently used herbal products
ular herbal medicine whose bioactive compound ginsenosides have concurrently with chemotherapy is needed to shed light on the molec-
been found to enhance antiproliferative effects when co‐ ular mechanisms of the synergy and amelioration of chemotherapy‐
administered with chemotherapeutics. In one study, panaxadiol was induced side effects by natural products and develop the best interven-
co‐administered with 5‐fluorouracil resulting in a significant increase tion for the clinical use of herbal‐drug combination therapy.
in the efficacy of cell cycle arrest in gastric cancer cells [30]. The Several efforts have gone into generating multiple data to elucidate
authors reported that the ginsenoside panaxadiol enhances efficacy the underlying mechanisms in the efficacy of herbal‐drug combination
through regulation of the cell cycle transition and induction of apopto- therapy and to showcase the health benefits of such treatment regi-
sis. In the study, panaxadiol arrests cancer cells at the G1 phase, mens (Table 1). Although most of these experimental studies have
whereas 5‐fluorouracil affects the cells in the S and G2/M phases. used in vitro cell lines or rodent in vivo models to explore mechanisms
The Ginseng species, Panax ginseng and 5‐fluorouracil both show an of herbal‐drug combination therapy, it is unlikely that data from most
affinity for caspase 3 in gastric cancer cells resulting in significant syn- of these studies will be predictive of effects in humans. Hence in‐depth
ergistic effects in combination therapy. More in‐depth research into scrutiny of herbal‐drug combination therapy using the idea model
the synergistic effect of P ginseng and 5‐fluorouracil showed enhanced including non‐human primates and the best platform technology that
nitric oxide which was identified as another possible mechanism in the will generate acceptable data is urgently needed to facilitate the clin-
inhibition of human cancer cell line BGC323 [30]. Nitric oxide has ical application of herbal‐drug combination therapy to combat the
been found to directly suppresses the growth of cancer cells by induc- ongoing fight against cancer. One such approach is the safety pharma-
ing G0/G1 phase arrest through the regulation of the Akt signalling cology evaluation of chemo‐herbal drug combination therapy for can-
pathway. Ginsenosides were also reported to increase nitric oxide pro- cer. The ICH guidelines S7A define safety pharmacology as tests for
duction by inducing phosphorylation of endothelial nitric oxide syn- essential life‐support organs, the central nervous system, the respira-
thase phosphorylation via the ER‐mediated PI3‐kinase/Akt pathway. tory system, and the cardiovascular system as core battery tests [36].
Besides, targeting the HER2 and ERK‐2 pathways to overcome drug Safety pharmacology is now increasingly required for the development
resistance, ginseng showed downregulation of Programmed death and clinical trial of new drugs [37]. To date, no studies have evaluated
ligand 1 (PD‐L1) in lung cancer cells [31]. The authors reported that the safety pharmacology of chemo‐herbal drug combination therapy
ginsenoside Rg3 inhibited cell growth and reduced resistance to cis- for cancer.
platin in the resistant cells. The researchers also found overexpression
of PD‐L1 in A549 / DDP cells relative to A549 cells. Ginsenoside Rg3
reduced the PD‐L1 expression caused by chemoresistance and restored 3. Clinical trials demonstrating the effectiveness of herbal
the cytotoxicity of T cells to cancer cells. NF‐κB p65 and Akt are medicine in reducing chemotherapy-induced toxicity and
involved in the overexpression of the PD‐L1 and inhibited by Rg3. enhancing synergistic effect
The bioactive compound panaxadiol saponins from Ginseng was
reported to possess hematopoietic growth factor‐like activity that pro- Vomiting and nausea are two of the most common side effects asso-
motes the proliferation and differentiation of HPCs in ciated with chemotherapy. Previous studies have shown some evi-
cyclophosphamide‐induced myelosuppressive mice. This activity was dence of the PD effect of herbal‐drug combination to combat
associated with the ability of the bioactive compound to regulate chemotherapy‐induced side effects (Table 2). For instance, 6‐
MEK/ERK protein kinases and extracellular signal‐regulated kinase gingerol (a major active ingredient extracted from ginger) was used
protein kinase, C‐kit, and GATA‐1 transcription factors [32]. as an anti‐emetic agent concomitantly with moderately to highly eme-

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togenic chemotherapy in a randomized double‐blind placebo‐ Mauktikyukta Praval Panchamruta during treatment with six rounds
controlled study. In the study, a total of 88 patients were randomized of chemotherapy. The third group received treatment with the same
to receive 6‐gingerol 10 mg or a placebo, twice a day for 12 weeks. The herbal drugs, but only after completing the sixth cycle of chemother-
authors confirmed that 6‐gingerol significantly improved the overall apy. The fourth group received additional Suvarnabhasmadi formula-
complete response rate together with increased appetite and quality tion, in combination with the above‐mentioned herbal drugs, after the
of life compared to the standard anti‐emetic treatment group [38]. sixth cycle of chemotherapy. The patients were assessed based on the
Marx et al. [39] reported similar positive treatment outcomes when Common Toxicity Criteria. Patients in groups two, three and four all
a standardized ginger extract was used concomitantly with moderate showed a significant increase in quality of life. Moreover, in all three
or highly emetogenic chemotherapy in a double‐blind, randomized groups that received Ayurvedic medicine, there was a significant
placebo‐controlled trial. The anti‐emetic properties of 6‐gingerol are improvement in nausea, appetite, constipation and fatigue compared
associated with its ability to inhibit neurokinin‐1, serotonin and to the control group.
chemotherapy‐induced trigger zone [38]. Myelosuppression with leukocytopenia, erythrocytopenia, and
The incidence of oral mucositis in cancer patients receiving thrombocytopenia are the most frequent and serious side effects
chemotherapy at standard doses is between 40 and 60 %, and at high among cancer patients undergoing chemotherapy. Ginsenoside Rg3
doses of chemotherapy, the incidence goes up to nearly 100 % [40]. was reported to improve the median survival time and reduce myelo-
Typically, oral mucositis causes soreness, bleeding, pain, difficulties suppression in advanced non‐small lung cancer patients receiving first‐
in swallowing and alteration of taste [41]. This can lead to a severe line chemotherapy during multicentre, large‐sample, randomized clin-
decrease in the quality of life of patients. Plantago ovata was reported ical trials [44].
to significantly prevent and treat oral mucositis in breast cancer Oxidative stress and energy metabolism imbalance are frequent
patients receiving chemotherapy regimens including adriamycin in a occurrences associated with chemotherapy‐induced cardiotoxicity.
double‐blind, randomized, controlled crossover trial [42]. The preven- Several herbal products have been shown to ameliorate ischemic
tion and treatment of oral mucositis by P. ovata were associated with myocardial injury and improve heart function when co‐administered
its anti‐inflammatory, antioxidant and anti‐allergic, and protective with chemotherapy. Injection of a Chinese herbal medicine Dan‐
effect on mucous membranes. Deshmukh et al. [43] assessed the effec- Hong was reported to restore doxorubicin‐induced cardiotoxicity in
tiveness of ayurvedic drugs to alleviate chemotherapeutic drug toxicity H9c2 cells by improving energy metabolism and reducing oxidative
and improve the quality of life of patients with various malignancies at stress [45]. Wu et al. [46] reported that fermented Cordyceps sinensis
various stages. Four groups of patients were enrolled on the study, of attenuated doxorubicin‐induced cardiotoxicity by inhibiting myocar-
which one group was treated with six rounds of chemotherapy alone, dial hypertrophy and myocardial damage, regulating systolic function
and the second group was treated with Mauktikyukta Kamdudha and and antioxidant enzyme system as well as improving cardiac energy

Table 2
Clinical evidence of herbal medicine ameliorates chemotherapy-induced toxicity and enhances the efficacy.

Name/ ingredient Dose Malignancy Patients Effect/Mechanism Reference

(Treatment
Herbal chemotherapy
group/
drug
control
group)

Xiaoaiping injection (Marsdenia 1 Platinum-based (Standard Non-small cell 70/70 Reduced chemotherapy-induced [79]
tenacissima) dose/day dose) lung cancer thrombocytopenia by Significantly improved
for and gastric platelet count.
10 days cancer

Curcumin 300 mg, Paclitaxel Breast cancer 75/75 Increased objective response rate and physical [72]
once per (80 mg/m2) performance after 12 weeks. Possibly reducing
week fatigue.
MB-6 (fermented soybean extract, NS leucovorin/5-fluorouracil Colorectal 72 No significant difference in the best overall [80]
green tea extract, Antrodia (Standard dose) response rate and overall survival between the
camphorata mycelia, spirulina, 2 groups. The MB-6 intervention significantly
grape seed extract, and curcumin lowered the disease progression rate and
extract) reduced the incidence of adverse events.
Ginger extract 160 mg/ Cisplatin (>50 mg/m2) Lung (49 %) 121/123 No differences were reported in terms of safety [81]
per and head and profile or compliance. The benefit of ginger
neck cancer intervention was recorded among female
(HNC; 35 %) patients in Functional Living Index Emesis
nausea score differences (day 6 − day 1).
Rikkunshito (JP Atractylodes Lancea 2.5 g CDDP 10/body i.v. on day Oesophagus 8/10 Rikkunshito intervention significantly lower [82,83]
Rhizome, Ginseng, Pinellia Tuber, three 1–5, 5-FU 370 mg/m2 on cancer the incidence of symptoms such as nausea,
Poria Sclerotium, Jujube, Citrus times a day 1–5 and docetaxel anorexia, and vomiting and QOL was also
Unshiu Peel, Glycyrrhiza, and day 25 mg/m2 on day 1 and 8. enhanced compared to the control group.
Ginger) Cisplatin Gastric cancer 5/5
Hangeshashinto NS Cisplatin and docetaxel Head and 40/40 Effectively ameliorate oral mucositis induced [84]
neck cancer by chemoradiation compared to the control.
Also, improved completion rates of
chemoradiation treatments with cisplatin.
Goshajinkigan 2.5 g mFOLFOX6 plus oxaliplatin Colorectal 29/44 Goshajinkigan intervention prevented [85]
orally 3 85 mg/m2, leucovorin cancer exacerbation of oxaliplatin-induced peripheral
times 400 mg/m2 and 5-FU neuropathy but no significant difference in
daily 2400 mg/m2 time to treatment failure and severe adverse
events between.

NS = Not specified; QOL = Quality of life.

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A. Okem et al. Medicine in Drug Discovery 17 (2023) 100147

metabolism. Platycodon gradiflorum was reported to exhibit cardiopro- 5. Conclusion

tective effects in early‐stage breast cancer patients undergoing
anthracycline‐based chemotherapy in a randomized control trial [47]. This review highlights efforts into understanding the mechanisms
Oxaliplatin has been used extensively as the first‐line chemothera- behind PD interactions of herbal‐drug combination therapy. Several
peutic agent for advanced colorectal cancer. However, the incidence of studies have shown the great potential of herbal products as adjuvant
oxaliplatin‐induced peripheral neurotoxicity is extremely common therapy to enhance synergy, reduce chemotherapy‐induced toxicity,
among patients between 82 and 98 % [48]. Kono et al. [49] conducted suppressed drug resistance, provides quick drug action, and enhance
a phase II double‐blind randomized, placebo‐controlled study in the quality of life of patients. Recent research has exploited the use
patients with advanced or recurrent colorectal cancer treated with of modern platform technology including in vitro and in vivo experi-
standard FOLFOX regimens in combination with goshajinkigan ments to elucidate the benefits/ or risks of herbal‐drug combinatory
(n = 44) or placebo (n = 45). The authors reported that goshajinkigan therapy to treat cancer. However, there is a limited corresponding out-
(a traditional Japanese herbal medicine) intervention appeared to come in clinical trials, thus, patients must be cautious in the use of
have an acceptable safety margin and significantly reduces the inci- herbal‐drug combination therapy for cancer treatment. Also, clinical
dence of neurotoxicity and delays the onset of grade ≥ 2 neurotoxici- trials reported in this review are mostly from Asia, hence there is a
ties without impairing FOLFOX efficacy. need for more reliable evidence from other parts of the world to pro-
In a phase‐I escalated clinical trial, curcumin (500 mg/day) was vide a global perspective on herbal‐drug combination therapy in the
administered with docetaxel (100 mg/m2) for seven days in patients management of cancer. Further studies using high‐level platform tech-
with advanced or metastatic breast cancer. The data revealed a promis- nology including safety pharmacology as well as multicentre clinical
ing biological response in the chemoprevention by reducing carci- trials are urgently needed to elucidate the risks and benefits of some
noembryonic antigen tumour markers compared to when the drug of the prominent herbal drugs used concurrently with
was used alone [50]. Darvishi et al. [51] reported significant biological chemotherapeutics.
activities among breast cancer patients pre‐treated with propolis one
week before standard chemotherapy compared to the placebo‐
6. Expert opinion
controlled group. In the study, the Propolis group (n = 26) showed
a marked decrease in pro‐inflammatory cytokines tumour necrosis fac-
The safety of chemo‐herbal drug combination therapy is now a
tor, interleukin‐2 and protein carbonyl (as a biomarker of oxidative
major concern for both health authorities and the public. Hence, safety
stress) compared to the placebo group (n = 24).
pharmacology evaluation of chemo‐herbal drug combination therapy
is urgently needed to elucidate any undesirable pharmacodynamic
4. Factors limiting the clinical application of herbal medicine as effect of such combination therapy. Preclinical evidence has shown
adjuvant therapy that chemo‐herbal drug combination therapy enhances therapeutic
efficacy through various mechanisms such as inducing apoptosis,
There is a surge of interest among cancer patients to use herbal reducing cell proliferation, cell cycle arrest as well as interfering with
medicine concurrently with chemotherapy treatment either for its relevant gene expression and protein signalling pathways in various
anticancer properties or as supportive care. However, the effectiveness cancer cell lines. However, it is important to highlight that the data
of chemo‐herbal drug combination therapy is not well‐documented as from some of the preclinical studies lack translational applications in
more studies are urgently needed. Another factor hindering the clinical the clinical use of chemo‐herbal drug combination therapy for cancer.
application of chemo‐herbal drug combination therapy is the poor To overcome these limitations, firstly, there is a need for an in‐depth
bioavailability of herbal drugs. For instance, resveratrol studies have mechanistic evaluation of chemo‐herbal drug combination therapy
limited clinical applications due to rapid metabolism being critically by adopting advanced methods including network‐based approach
below the therapeutical relevant level in the bloodstream, despite optimization using state‐of‐the‐art facilities that will generate efficient
showing extremely promising antiproliferative effects in preclinical and reliable data predictive in humans. Secondly, high‐level platform
studies [52–54]. Similarly, curcumin as one of the most popular herbal technology including safety pharmacology tests as well as multicentre
medicines is faced with the problem of poor absorption, rapid metabo- clinical trials are urgently needed to fast‐track the adoption of chemo‐
lism and systemic elimination culminating in its poor bioavailability herbal drug combination therapy for cancer treatment. All these efforts
thereby limiting its clinical applications [55]. In summary, several fac- should be geared toward bridging the gap between experimental data
tors have been identified as limiting factors hampering the translation and the clinical application of herbal drugs as adjuvant therapy in the
of preclinical data into the clinical application of herbal medicine as management of cancer.
adjuvant therapy:
Authors’ contributions
1. Lack of quality control and standardization of herbal medicine.
2. Poor bioavailability of herbal drugs. AO conceptualized the research idea, ML and CH gathered the data,
3. Herbal product contains multi‐ingredients with inherent complex- AO prepared the manuscript, RH improved the narrative. All authors
ity in their interactions with other molecules. have read and approved the last version of the manuscript.
4. Cell line models employ in in vitro assays lack tumour
microenvironment.
5. The human body is complex compared to animal models frequently Funding
used in preclinical studies.
6. Need for an in‐depth, high‐content screening platform technology This research did not receive any specific grant from funding agen-
including safety pharmacology to elucidate unknown molecular cies in the public, commercial, or not‐for‐profit sectors.
mechanisms by which herbal medicines produce a synergistic
effect/ or ameliorate chemotherapy‐induced toxicity. Declaration of Competing Interest
7. Lack of high‐quality, multicentre clinical trials to assess the effec-
tiveness of herbal medicine to attenuate the chemotherapy‐ The authors declare that they have no known competing financial
induced side effects and improve efficacy. interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.

6
A. Okem et al. Medicine in Drug Discovery 17 (2023) 100147

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