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Review

Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action

by
Abdul Waheed Khan
1,
Mariya Farooq
1,
Muhammad Haseeb
1,2 and
Sangdun Choi
1,2,*
1
Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea
2
S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Korea
*
Author to whom correspondence should be addressed.
Cells 2022, 11(8), 1326; https://doi.org/10.3390/cells11081326
Submission received: 17 March 2022 / Revised: 31 March 2022 / Accepted: 11 April 2022 / Published: 13 April 2022
(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)
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Abstract

:
Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants’ bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals.

1. Introduction

Cancer is a challenging disease and is the main cause of mortality worldwide; however, its impact is not evenly distributed. The cancer burden in developed and underdeveloped countries has increased over time owing to a variety of factors, including aging and growing populations, rapid socioeconomic growth, and changes in the incidence of risk factors. Owing to the growth and aging of the world population, cancer is showing reduced survival rates in many countries [1,2]. Cancer is a complex disease involving uncontrolled growth and proliferation of cells in tissues, resulting in cell aggregation locally (tumor), and it can spread to an entire organ or even to other neighboring tissues systemically (metastasis) [3]. The uncontrolled cell behavior can be caused by genetic or epigenetic changes in oncogenes involved in cell proliferation or cell death regulation [4]. The incidence and mortality rates of cancer are continuously increasing. According to a study published in 2020, the global incidence of cancer cases was 247.5, whereas the mortality rate was 127.8 per 100,000 people. Developed countries, such as Japan, Australia, New Zealand, Germany, Canada, and France, topped the list in cancer incidence and mortality rates [2]. Furthermore, breast cancer had the highest incidence rate of 11.7%, while lung cancer had the highest mortality rate of 18% [5]. The worldwide estimated incidence and mortality rates of different cancers are shown in Table 1, and the percentages of incidence and mortality of different types of cancers are shown in Figure 1.
Several pathways are involved in cancer development, including the VEGF receptor pathway that can activate the RAS/RAF/MEK/ERK pathway [6] and the fibroblast growth factor (FGF) receptor pathway that activates multiple downward pathways, including the PI3K/Akt/mTOR, RAS/RAF/MEK/ERK and signal transducer and activator of transcription (STAT) pathways [7]. Reactive oxygen species (ROS) can activate the Akt/mTOR and AMPK signaling systems to induce cancer [8]. Wnt/β-catenin also plays a role in the development of multiple cancers [9]. Some important cancer-causing pathways and targets of the anticancer activity of phytochemicals are presented in Figure 2.
Since ancient times, herbal medicines have been used in health care systems. Research conducted to confirm the effectiveness of these medicines led to the discovery and development of plant-based medications. Local communities use medicinal plants to treat most diseases owing to lack of access to modern medication. In the past few decades, increasing evidence has revealed the remarkable potential plant-based therapeutics. Compared with synthetic medicines, medical plants have therapeutic potential with fewer side effects and lower costs [10].
Phytochemicals are plant-derived secondary metabolites. Based on epidemiological, in vitro, in vivo, and clinical trial data, a plant-based diet can lower the risk of many chronic diseases (e.g., neurological diseases, cardiovascular disease, diabetes, and cancer) owing to the action of bioactive plant constituents or phytochemicals [11].
Despite significant progress in the prevention and treatment of cancer, major gaps still exist, and further improvements are warranted. Modern chemotherapy has several side effects that impede the progress of cancer treatment and lead to other serious health problems. The development of integrated research systems and advanced screening procedures for plant bioactive components has ushered in a new era of phytochemical discoveries for the prevention and treatment of complex diseases such as cancer. Bioactive compounds such as berberine, curcumin, crocetin, colchicine, gingerol, lycopene, kaempferol, resveratrol, vincristine, and vinblastine have demonstrated remarkable anticancer potential [4]. Using modern and novel research approaches, more plant-derived constituents might be discovered to prevent and treat advanced-stage cancer without significant side effects.
In this review, we highlight phytochemicals that have been reported as anticancer agents and their putative mechanisms of action in cancer treatment and summarize in vitro, in vivo, and clinical trial data on these phytoconstituents.

2. Methodology

Data Collection

Articles on phytoconstituents with anticancer activity were searched for using specific keywords such as “phytochemicals”, “plant-derived constituents”, “plant-based medicine”, “antitumor”, “cytotoxic”, “cancer epidemiology,” and “incidence” from online research databases such as PubMed, Web of Science, Medline, Google Scholar, and Science Direct and downloaded. The articles were entirely read, and data on phytochemicals with anticancer properties were collected and tabulated in Table 2.

3. Data Analysis

A total of 78 plant-derived compounds belonging to various families were found to have significant anticancer activity; tested via in vitro and in vivo experiments. Most of these phytochemicals were alkaloids 19 (24%), flavonoids 14 (18%), terpenes 12 (15%), isoflavones 5 (6%), and phenols 5 (6%) (Figure 3).
Multiple phytochemicals were found to exhibit activity against multiple cancers. Most of the phytochemicals were found to be effective against breast (55), lung and colon (53 each), prostate (45), liver (30), ovarian (27), gastric (24), pancreatic (18), cervical (14), bladder (13), skin (11), oral (9), kidney (7), esophageal and thyroid (6 each), bile duct and brain (5 each), and miscellaneous (10) cancers (Table 3).
Of the total phytochemicals, lycopene was found to exhibit activity against 10 different types of cancer; baicalin, corosolic acid, plumbagin, shikonin, and thymoquinone displayed activity against 9; erianin, evodiamine, gallic acid, and gossypol exerted effects against 8; apigenin, curcumin, luteolin, oridonin, resveratrol, and silibinin had effects against 7; and other phytochemicals showed activity against six or less than six types of cancer (Table 4).
Several plant-derived active constituents, such as vincristine, vinblastine, paclitaxel, have been approved by the FDA as therapeutics for different cancers. Several other phytochemicals are currently in clinical trials for the treatment of various cancers (Table 5), and their structures are given (Figure 4).

3.1. Important Anticancer Phytochemicals from the Clinical Trials and Their Structure–Activity Relationship Data

According to a scientific report, phytochemicals may have substantial anticancer properties. Approximately 50% of the drugs approved between 1940 and 2014 were obtained directly or indirectly from natural sources [403]. Some important phytochemicals, currently in clinical trials, that showed good in vitro and in vivo potentials in different types of cancers are described below.

3.2. Curcumin

Curcumin, a lead phytochemical extracted from Curcuma longa, inhibits the growth of human glioma cells by inhibiting numerous cellular and nuclear factors. Curcumin increases the expression of various genes and their products, including p16, p21, and p53, Bax, EIK-1, Erk, c-Jun N-terminal kinase, early growth response protein 1, and caspases-3, -8, and -9, while reducing the expression of Bcl-2, pRB, cyclin D1, mTOR, NF-κB, and p65 [404].
The potent antioxidant property of curcumin is responsible for many of its medicinal actions, including its anticancer activity. The majority of natural antioxidative chemicals are either phenolic or -diketone compounds. But curcumin, is one of the few antioxidative compounds that has both phenolic hydroxy and -diketone groups in a single molecule [405].
In one study, researchers investigated the importance of the phenolic hydroxy groups, and other substituents in the phenyl rings of curcumin and its analogs, to their antioxidant activities by using the three antioxidant bioassays (free radical scavenging activity by the ABTS method, free radical scavenging activity by the DPPH method, and inhibition of lipid peroxidation). In all the three assays, the phenolic curcumin analogs were more potent than the non-phenolic analogs, indicating that the phenolic groups are critical for antioxidant action. Curcumin is thought to be a classic phenolic chain-breaking antioxidant, donating H atoms from phenolic groups [406,407].
In another research study, curcumin analogs were synthesized or isolated from natural sources and evaluated for AR inhibitory activity in prostate cancer cell lines. Among these analogs, few exhibited the greatest inhibitory activity against the transcription of AR, while others showed less or no activity. Based on the bioassay results, researchers showed the SAR of curcumin analogs as anti-AR reagents as follows. (1) The conjugated β-diketone moiety is required for the activity. Saturating or removing the C=C bonds resulted in a decrease or loss of activity, while converting the β-diketone moiety to pyrazole leads to a reduction or loss of activity. (2) When the methylene group in the linker was not substituted, the inhibitory activity was significantly increased by substituting the phenolic hydroxy groups with methoxy or methoxycarbonylmethoxy groups. (3) Adding an ethoxycarbonylethyl group to the central methylene group dramatically improved the anti-AR action of curcumin when the phenyl ring substitution was retained. (4) Anti-AR activity was lost in all electron-withdrawing substitutions in the phenyl rings. The exact mechanism through which curcumin analogs block AR transcription is undisclosed [408,409,410,411]. Further initiatives need to be taken to extend the SAR and enhance anti-AR activities of curcumin.

3.3. Epigallocatechin Gallate (EGCG)

EGCG is the chief constituent of green tea that can restore the expression of tumor suppressor genes such as retinoid X receptor-alpha in breast cancer, ultimately preventing breast cancer by binding to other high-affinity proteins such as Zap-70 [412]. EGCG is also found to be effective against lung, colon, and prostate cancers by inducing DNA damage and AMPK signaling and inhibiting Notch1, MMP-2/9, and β-catenin expression [115,117,331].
In EGCG structure, the three aromatic rings are connected by a pyran ring. The structure of EGCG is thought to be responsible for its health-promoting properties. The potent antioxidant effect of catechins is achieved through quinone and semiquinone synthesis, which involves oxidation of phenolic groups with atomic or single electron transfer in the periphery aromatic rings [413,414]. These rings have been linked to a decrease in proteasome activity. Protected analogues are the only ones that suppress proteasome activity. In vitro, dehydroxylation of either one or both periphery aromatic rings, inhibits proteasome inhibitory activity. Furthermore, the apoptotic cell death is induced by these protected analogues in tumor cell-specific manure. These findings showed that the periphery aromatic rings peracetate protected EGCG analogues, have a lot of potential as anti-cancer and cancer-prevention drugs [415]. The first structure–activity correlations between EGCG and heat-shock protein 90 were described and analyzed by Khandelwal et al. His findings suggest that phenolic groups on the aromatic ring, adjacent to pyrin ring, are useful in inhibiting heat-shock protein 90, whereas phenolic substituents on the faraway periphery ring are unfavorable [416]. Finally, when compared to catechins without the 5′-hydroxyl group, the hydroxyl group at the 5′-position in the upper aromatic ring inhibited urease up to 100-fold and also prevented Helicobacter pylori growth in the gut [417].

3.4. Genistein

Genistein, a potent anticancer compound, can be isolated from soybeans, lentils, chickpeas, and beans. It exhibits a pro-apoptotic effect in colon cancer and has a variety of functions: it upregulates Bax and p21, blocks topoisomerase II and NF-κB, and increases the expression of antioxidant enzymes such as glutathione peroxidase [418].
Genistein is a natural flavonoid that has been found to interact with several biological targets. After orally administration, its quick breakdown into inactive metabolites and rapid excretion from the body, are the main disadvantages of using genistein as a chemotherapeutic agent [419]. Therefore, to obtain better bioavailability compounds than genistein, a delayed compound metabolism is required. In one study, it was found that the proportion of metabolites was affected by the nature of the glycosidic bond. The metabolization of genistein derivatives with a more stable C-glycosidic bond was slower than derivatives with an O-glycosidic bond. It was also reported that linking a sugar moiety to the genistein structure increases its metabolism time in the body [420].
In another research work, it has been found that in comparison to the genistein parent molecule, novel genistein glycosyl derivatives with an O-glycosidic or C-glycosidic linkage have better antiproliferative effects. [421,422]. The C-7 or C-4′-hydroxyalkyl ethers of genistein (intermediates in the glycoconjugates synthesis), are found to be more active in preventing tumor cell growth than genistein. Furthermore, biological investigations have also revealed that derivatives with a substituent at the C-7 position inhibit the cell cycle in the G2 phase, whereas derivatives with a substituent at the C-4′ position disrupt the cell cycle in the G1 phase. [421]. It is concluded that the structural modification (hydroxyl group etherification) of genistein, successfully improved its antiproliferative activity.

3.5. Lycopene

Lycopene is a vibrant red pigment found in tomatoes, red carrots, watermelons, and red papaya. It plays a key role in targeting the PI3K/Akt pathway in stomach and pancreatic cancers by suppressing the expression of Bcl-2, an Erk protein. In breast, endometrial, prostate, and colon cancers, lycopene upregulates antioxidant enzymes GSH, GPxn, and GST and eliminates oxidative injury induced by toxins. Lycopene has been demonstrated to affect the growth and progression of HT-29 cells in culture and tumors in animal models by interfering with numerous cellular signal transduction pathways such as those of JNK and NF-κB. Lycopene also prevents infiltration, metastasis, and multiplication of human SW480 colon cancer cells by inhibiting JNK and NF-κB activation, and suppressing the production of COX-2, IL-1, IL-6, IL-10, and iNOS [423,424].
Carotenoids promoted the expression of phase II enzymes by activating the electrophile/antioxidant response element (EpRE/ARE) transcription pathway. Phase II detoxifying enzymes are a key biological method for minimizing cancer risk. By disrupting the inhibitory effect of Keap1 on Nrf2, the key EpRE/ARE activating transcription factor; certain electrophilic phytonutrients have been demonstrated to stimulate the EpRE/ARE system. However, carotenoids like lycopene are hydrophobic, lacking an electrophilic group, which is unlikely to activate Nrf2 and the EpRE/ARE system directly. The active mediators in lycopene’s activation of the EpRE/ARE system are carotenoid oxidation products. Researchers discovered the main structure–activity rules for EpRE/ARE activation using a series of described mono- and di-apocarotenoids that might potentially be produced from in vivo metabolism of carotenoids (lycopene). Such as active molecules are the aldehydes, not acids; the methyl group on the terminal aldehyde, which regulates the reactivity of the conjugated double bond, is responsible for the activity, and the main chain of the molecule is constituted of the dialdehyde’s optimum length (12 carbons). The apocarotenals suppressed breast and prostate cancer cell proliferation with an efficacy comparable to that of EpRE/ARE activation. These findings may provide a molecular explanation for the cancer-preventive properties of carotenoids like lycopene [425,426].

3.6. Resveratrol

Resveratrol, a naturally occurring polyphenol, is found in peanuts, mulberries, grapes, blueberries, and bilberries. It plays a significant role in the treatment of different types of cancers, including colorectal, breast, pancreatic, liver, lung, and prostate cancers, by increasing the expression of Bax and p53 and decreasing the expression of NF-κB, AP-1, Bcl-2, MMPs, cyclins, COX-2, cyclin-dependent kinases, and cytokines. Resveratrol has been recognized to impede angiogenesis and suppress VEGF by decreasing MAP kinase phosphorylation [418].
A research study was carried out to find the structure–activity relationship of resveratrol in cancer. It was observed that the number and position of free phenolic hydroxyl groups have a key role in the anticancer activities of resveratrol. For this purpose, the researchers used different analogs of resveratrol having different phenolic hydroxyl groups for their anticancer activities in T24 cells. They found that the oxyresveratrol (3-OH glycosylated RV, having an extra -OH group than RV) has greater inhibitory effect that RV but polydatin (3-OH glycosylated RV, lack of one -OH group) has a lesser effect than RV. This showed that the increased number of phenolic hydroxyl groups are responsible for the anticancer activity of RV [427]. Herath et al. proved the theory by discovering that when the hydroxyl groups in RV were replaced, the drug’s pharmacological activity decreased [428]. Furthermore, Miksits et al. found that all of RV’s sulfated metabolites were less effective against various cancer cell lines [309]. This suggests that the anti-tumor efficacy of RV can be affected by the conjugation of phenolic hydroxyl groups with sulfuric acid. Hence, again it is proved that the free phenolic hydroxyl groups are important for antitumor effect of RV.
Currently, several investigations on plant-based drugs to treat cancer are ongoing. Some well-known and effective phytochemicals, such as vincristine, were approved by the FDA in 1963 to treat acute leukemia (brand name, Oncovin). Furthermore, paclitaxel was approved for the treatment of metastatic breast cancer, advanced lung cancer, and pancreatic cancer in 2005, 2012, and 2013, respectively, under the brand name, Abraxane. Curcumin, lycopene, and capsaicin, which are under phase-III trials for prostate and breast cancers, are promising candidates for cancer therapy. Quercetin, genistein, silibinin, and EGCG are undergoing clinical trials or treatment for various types of cancers.
This study of anticancer plant-derived phytochemicals will help ethnomedicine and ethnopharmacology investigations, resulting in better outcomes for the medical potential of natural resources. Various phytochemicals highlighted in this review could be further investigated in clinical trials, enabling the availability of more effective anticancer medicines with fewer adverse effects. This study will be beneficial to researchers working on or interested in the discovery of plant-based medicines for treatment of various cancers.

4. Conclusions

Researchers have found multiple synthetic drugs for the treatment of cancer, but anticancer drugs are costly and have some major adverse effects like anemia, vital organs damage, and hair and nail loss. Keeping in mind these drawbacks, we searched multiple papers on natural anticancer compounds, their mechanisms, clinicals trials and SAR data of important phytochemicals. The epidemiology data showed that the breast and lung cancers have the highest mortality and prevalence rates. In this study, we found that majority of anticancer compounds belong to alkaloids and flavonoids classes, and the highest number of phytochemicals were found to be effective against breast and lung cancers, which give us a chance to try these phytochemicals in clinical trials and discover some plant-based drugs that control these high spreading cancers. To discover effective anticancer treatments with less side effects and less cost, the world must rely upon, and conduct more research on natural resources, especially plants and their active constituents.

Author Contributions

Conceptualization, methodology, original draft preparation, article writing, visualization, A.W.K. and S.C., software work, validation, data curation, review, and editing, M.F. and M.H., resources, review and editing, supervision, project administration, funding acquisition, S.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Korea Drug Development Fund, funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN21C1058). This work was also supported by the National Research Foundation of Korea [2022M3A9G1014520, 2019M3D1A1078940 and 2019R1A6A1A11051471]. The sponsor had no role in the study design; collection, analysis, and interpretation of the data; writing of the report; and the decision to submit the article for publication.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AIFApoptosis-inducing factorMUC1-CMucin 1, cell surface associated protein
Apaf-1Apoptotic protease activating factor 1NAF-1Nuclear assembly factor 1
ATF4Activating transcription factor 4NAG-1NSAID activated gene 1
Bcl-XLB-cell lymphoma-extra largeNBR1Neighbor of BRCA1 gene 1
CCL2Chemokine (C-C motif) ligand 2 Nrf2Nuclear factor erythroid 2–related factor 2
CDKCyclin-dependent kinases PD-L1Programmed death-ligand 1
CHOPC/EBP homologous proteinPKM2Pyruvate kinase M2
CREBcAMP-response element binding proteinPLK1Polo-like kinase 1
CXCR4C-X-C chemokine receptor type 4PPARγPeroxisome proliferator- activated receptor gamma
DR5Death receptor 5PTENPhosphatase and tensin homolog deleted in chromosome 10
ER Endoplasmic reticulumRafRapidly accelerated aibrosarcoma
FAKFocal adhesion kinaseRASSF6Ras-association domain family
FOXA2Forkhead box protein A2RHAMMHMMR hyaluronan-mediated motility receptor
GADD45BGrowth arrest and DNA-damage-inducible, beta proteinRhoARas-homolog family member A
GLUT1Glucose transporter 1RIP1Receptor interacting protein 1
H2AXH2A histone family member XROCK1Rho-associated protein kinase 1
HIF-2αHypoxia inducible factor 2 alphaROSReactive oxygen species
HMGB1High mobility group box 1 proteinSGK1Serum/glucocorticoid regulated kinase 1
HOXD3Homeobox D3Skp2S-phase kinase associated protein 2
HSP90Heat shock protein 90TASK-3Two-pore-domain acid sensitive K+ channel 3 TASK-3
hTERTHuman telomerase reverse transcriptaseTGF-β1Transforming growth factor-beta1
iNOSInducible nitric oxide synthaseTNF-αTumor necrosis factor alpha
IκBαIkappaB alphaTop1Topoisomerase 1
IκK-αInhibitory-κB kinase alphaTRAILTNF-related apoptosis-inducing ligand
JNKJun N-terminal kinaseTRIM16Tripartite motif-containing protein 16
Keap1Kelch-like ECH-associated protein 1uPAUrokinase-type plasminogen activator
LOXLysyl oxidaseUSP14Ubiquitin specific peptidase 14
MEKMAPK/ERK kinaseWntWingless-related integration site
mTORMammalian target of rapamycinXIAPX-linked inhibitor of apoptosis protein

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Cells 11 01326 g001 550
Figure 1. Incidence and mortality rates of different cancer types in 2020. Percent increases in incidence and mortality rates of different cancers are shown, with breast, lung, prostate, colorectal, and stomach cancers having the highest incidence and mortality rates. Cancers with low percent incidence and mortality rates are combined as miscellaneous cancers.
Figure 1. Incidence and mortality rates of different cancer types in 2020. Percent increases in incidence and mortality rates of different cancers are shown, with breast, lung, prostate, colorectal, and stomach cancers having the highest incidence and mortality rates. Cancers with low percent incidence and mortality rates are combined as miscellaneous cancers.
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Cells 11 01326 g002 550
Figure 2. Important cellular mechanisms involved in cancer and mechanisms of action of phytochemical drugs. Growth factors, such as vascular endothelial growth factor and fibroblast growth factor, bind with their respective receptors, resulting in their phosphorylation, followed by the activation of downstream signaling pathways, such as the PI3K/Akt, PLCγ, and STAT pathways. Akt activates IKK, which is responsible for the activation of the NF-κB signaling and mTOR pathway; IKK exerts its effect on cells by regulating the hypoxia-induced factor. ROS activates the Akt and AMP-activated protein kinase (AMPK) pathways by inducing endoplasmic reticulum stress. AMPK activates the tumor suppressor transcription factor (FOX O) and inhibits the action of mTOR. Wnt proteins suppress glycogen synthase kinase-3β (GSK-3β) by binding to frizzled receptors, disrupting the β-catenin complex (destructive complex). β-catenin accumulates in the cytoplasm, translocates to the nucleus, and induces cell proliferation, which promotes cancer by activating Wnt-regulated genes. Different phytochemicals act on different targets to exhibit anticancer activity.
Figure 2. Important cellular mechanisms involved in cancer and mechanisms of action of phytochemical drugs. Growth factors, such as vascular endothelial growth factor and fibroblast growth factor, bind with their respective receptors, resulting in their phosphorylation, followed by the activation of downstream signaling pathways, such as the PI3K/Akt, PLCγ, and STAT pathways. Akt activates IKK, which is responsible for the activation of the NF-κB signaling and mTOR pathway; IKK exerts its effect on cells by regulating the hypoxia-induced factor. ROS activates the Akt and AMP-activated protein kinase (AMPK) pathways by inducing endoplasmic reticulum stress. AMPK activates the tumor suppressor transcription factor (FOX O) and inhibits the action of mTOR. Wnt proteins suppress glycogen synthase kinase-3β (GSK-3β) by binding to frizzled receptors, disrupting the β-catenin complex (destructive complex). β-catenin accumulates in the cytoplasm, translocates to the nucleus, and induces cell proliferation, which promotes cancer by activating Wnt-regulated genes. Different phytochemicals act on different targets to exhibit anticancer activity.
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Cells 11 01326 g003 550
Figure 3. Numbers and percentages of anticancer phytochemicals belonging to different phytochemical classes. In this review, most phytochemicals were found to be constituted of alkaloids followed by flavonoids, terpenes, flavones, and phenols. The phytochemicals classes that have less than two phytochemicals are included in the miscellaneous class.
Figure 3. Numbers and percentages of anticancer phytochemicals belonging to different phytochemical classes. In this review, most phytochemicals were found to be constituted of alkaloids followed by flavonoids, terpenes, flavones, and phenols. The phytochemicals classes that have less than two phytochemicals are included in the miscellaneous class.
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Cells 11 01326 g004 550
Figure 4. Structures of anticancer phytochemicals approved by FDA or in clinical trials.
Figure 4. Structures of anticancer phytochemicals approved by FDA or in clinical trials.
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Table
Table 1. Estimated worldwide incidence and mortality rates (per 100,000 people) of all cancer types in 2020.
Table 1. Estimated worldwide incidence and mortality rates (per 100,000 people) of all cancer types in 2020.
Continents Incidence Rank Mortality Rank
Worldwide 247.5 – 127.8 –
Asia 204.8 – 125.2 –
Japan 813.3 1 332.2 3
China 315.6 57 207.5 42
India 96 121 61.5 122
South Korea 449.2 42 172.8 56
Europe 587.4 – 261.1 –
Germany 750.2 4 300.9 10
France 716.9 9 284.4 17
Italy686.8 13 289.0 15
North America693.2 – 189.6 –
USA689.312185.0 54
Canada726.9 7 229.7 33
South America224.8 – 109.1 –
Brazil278.6 63122.3 72
Argentina289.6 60155.0 63
Colombia222.5 75108.1 81
Africa82.7 – 53.1 –
South Africa182.4 8395.8 87
Morocco 160.8 9395.5 88
Ethiopia 67.3 15845.1 155
Australia784.4 2 189.2 51
New Zealand745.2 5 217.9 38
Table
Table 2. Plant-derived phytochemicals with potential anticancer properties, and their mechanisms of action.
Table 2. Plant-derived phytochemicals with potential anticancer properties, and their mechanisms of action.
Sr #PhytochemicalsChemical
Nature		Plant’s Source/Origin Chemical
Structure		M: Weight (g/mol)Cancer TypeStudy TypeTargets and Mechanisms
1Allicin ThioesterAllium sativumC6H10OS2162.3Lung cancerIn vitroDownregulation of VEGF expression [12]
Gastric cancerIn vitro Enhanced expression of p38 and cleavage caspase-3 [13]
Oral cancerIn vitroUpregulation of and cleaved caspase-3 [14]
Brain cancerIn vitroElevation in Fas/FasL expression [15]
2AloperineAlkaloidSophora
alopecuroides		C15H24N2232.36Ovarian cancerIn vitroReactive oxygen species activation [16]
Thyroid cancerIn vitroSuppression of Akt pathway and downstream B-cell lymphoma (Bcl-2) expression [17]
Prostate cancerIn vitro, in vivoInhibition of Akt and ERK phosphorylation [18]
Bladder cancerIn vitroDownregulation of Ras, p-Raf1 and p-Erk1/2 expression [19]
Colon cancerIn vitroInhibition of JAK/Stat3 and PI3K/Akt pathways [20]
Bones cancerIn vitro Suppression of PI3K/AKT signaling [21]
3AlpinumisoflavoneIsoflavoneDerris eriocarpaC20H16O5336.3Colon cancerIn vitro Blockage of DNA repairing [22]
Esophageal cancerIn vitro, in vivo, ex-vivo Upregulation of miR-370 and suppression of PIM1 signaling [23]
Brain cancerIn vitroSuppression of glycolysis and cyclin D1 expression and activation of caspase-9 [24]
4AmygdalinDiglucosideRosaceae kernelsC20H27NO11 457.4Bladder cancerIn vitro Modulation of β1 or β4 integrin expression [25]
Breast cancerIn vitro Downregulation of Bcl-2, upregulation of Bax and p38 MAPK signaling pathways [26]
Prostate cancerIn vitro Activation of caspase-3 through downregulation of Bcl-2 and up-regulation of Bax [27]
Cervical cancerIn vitro Downregulation of Bcl-2 and upregulation of Bax protein [28]
5AndrographolideDiterpenoidAndrographis
paniculata		C20H30O5350.4Colon cancerIn vitro Increase intracellular ROS level [29]
Skin cancerIn vitro Activation of JNK and p38 signaling pathway [30]
Breast cancerIn vitro, in vivo Suppressing of COX-2 and VEGF pathway [31]
Prostate cancerIn vitro, in vivo Facilitate DNA damage [32]
Bile duct cancerIn vitro Suppression of Claudin-1 via p-38 pathway [33]
Ovarian cancerIn vitro Upregulation of TIMP1 expression [34]
6ApigeninFlavonoidMatricaria
chamomilla		C15H10O5270.24Colon cancerIn vitro, in vivo Inhibition of the Mcl-1, AKT, and ERK pro-survival regulators [35]
Lung cancerIn vitro, in vivoInhibition of NF-κB, AKT and ERK pathway [36]
Liver cancerIn vitro, in vivoInhibition of PI3K/Akt/mTOR signaling [37]
Pancreatic cancerIn vitro Through G2/M cell cycle arrest [38]
Breast cancerIn vitro Inhibition of YAP/TAZ activity [39]
Prostate cancerIn vitro, in vivo Suppression of NF-κB/p65 expression [40]
Bone cancerIn vitro Suppression of Wnt/β-catenin signaling [41]
7 ArtemisininAlkaloidArtemisia annuaC15H22O5282.33Colon cancerIn vitro and in vivoIncrease in ROS production [42]
Kidney cancerIn vitro, in vivo Inhibition of AKT signaling [43]
Ovarian cancerIn vitro, in vivo Suppression of AKT/ERK/mTOR pathway [44]
Gallbladder cancerIn vitro, in vivo Inhibition of ERK1/2 pathway [45]
8Baicalein FlavonoidScutellaria
baicalensis		C15H10O5270.24Lung cancerIn vitro, in vivo Suppression of VEGF, FGFR-2, and RB-1 pathways [46]
Colon cancerIn vitro Activation of caspase-3 [47]
Bladder cancerIn vitro, in vivo Inhibition of cyclin B1, MMP-2 and MMP-9 mRNA expressions [48]
Pancreatic cancerIn vitro, in vivo Increase caspase-3 and Bax, while decrease survivin and Bcl-2 expressions [49]
Liver cancerIn vitro Suppression of PI3K/Akt pathway [50]
Prostate cancerIn vitro Inhibition of caveolin-1/AKT/mTOR pathway [51]
Breast cancerIn vitro, in vivo Activation of PAX8-AS1-N activation [52]
Ovarian cancerIn vitro, in vivo Inhibition of YAP and RASSF6 expressions [53]
Skin cancerIn vitro, in vivo Inhibition of glucose uptake and metabolism of tumor cells [54]
9BerbamineAlkaloidBerberis amurensisC37H40N2O6608.7Blood cancer In vitro Upregulation of caspase-3 and downregulation of MDR-1 gene expression [55]
Liver cancerIn vitro, in vivo, ex vivo Inhibition of Ca2+/Calmodulin-dependent protein Kinase II expression [56]
Ovarian cancerIn vitro, in vivoInhibition of Wnt/β-catenin signaling [57]
Colon cancerIn vitro Inhibition of MEK/ERK signaling [58]
Head & neck cancerIn vitro Inhibition of STAT3 activation [59]
10CapsaicinCapsaicinoidCapsicum annuumC18H27NO3 305.4Breast cancerIn vitro, in vivoDownregulation of FBI-1-mediated NF-κB pathway [60]
Lung cancerIn vivo Downregulation of MMP-2 and -9 levels [61]
Prostate cancerIn vitro Increases protein light chain 3-II (autophagy marker) and ROS levels [62]
Colon cancerIn vitro Stabilization and activation of p53 [63]
Esophageal cancerIn vitro Decrease hexokinase-2 (HK-2) expression [64]
Skin cancerIn vitro Downregulation of PI3-K/Akt/Rac1 pathway [65]
11CepharanthineAlkaloidStephania cepharanthaC37H38N2O6606.7Colon cancerIn vitro Upregulation of p21Waf1/Cip1 pathway [66]
Breast cancerIn vitro Inhibition of AKT/mTOR signaling [67]
Ovarian cancerIn vitro Increases expression of p21Waf1 and decreasing expression of cyclins A and D proteins [68]
Liver cancerIn vitro Activation of JNK1/2 signaling and downregulation of Akt pathway [69]
12Chlorogenic AcidEster Etlingera elatiorC16H18O9354.31Liver cancerIn vitro, in vivo Inhibition of DNMT1 expression [70]
Colon cancerIn vitro Activation of PARP-1, and caspase-9 [71]
Breast cancerIn vitro Upregulation of Bax and downregulation of Bcl-2 expressions [72]
13ColchicineAlkaloidColchicum
automnale		C22H25NO6399.4Gastric cancerIn vitro, in vivo Induce caspase-3-mediated mitochondrial apoptosis [73]
Hypopharyngeal cancerIn vitro, in vivo Inhibition of phosphorylated FAK/SRC complex and paxillin [74]
Breast cancerIn vitro Inhibition of MMP-2 expression [75]
Colon cancerIn vitro Decrease in AKT phosphorylation [76]
14Combretastatin A4StilbeneCombretum caffrumC18H20O5 316.3Lung cancerIn vitro, in vivo Disruption of microtubule assembly [77]
Bladder cancerIn vitro, in vivo Activation of caspase-3 and reduction in BubR1 and Bub3 expressions [78]
Bone cancerIn vitro Inhibition of NDRG1 [79]
15Corosolic acidTripernoidLagerstroemia
speciosa		C30H48O4472.7Lung cancerIn vitro, in vivo Inhibition of VEGFR2 kinase activity [33]
Colon cancerIn vitro, in vivo Inhibition of HER2/HER3 receptors’ heterodimerization [80]
Gastric cancerIn vitro Activation of AMPK pathway [81]
Liver cancerIn vitro, in vivo, ex vivo Inactivation of CDK19/YAP/O-GlcNAcylation pathway [82]
Prostate cancerIn vitro, in vivo Activation of IRE-1/JNK, PERK/CHOP and TRIB3 [83]
Cervical cancerIn vitro Downregulation of PI3K and Akt signaling [84]
Kidney cancerIn vitro Induction of lipid ROS [85]
Breast cancerIn vitro Increase in ROS production and decrease in VEGF concentration [86]
Bladder cancerIn vitro, in vivo Upregulation of SQSTM1/P62, NBR1, and UBB expression [87]
16CrocetinCarotenoidCrocus sativusC20H24O4328.4Prostate cancerIn vitro, in vivo Induce DNA damage and apoptosis [88]
Colon cancerIn vitro Upregulation FAS/FADD death receptor [89]
Pancreatic cancerIn vitro, in vivo Upregulation of Bax and downregulation of Bcl-2 protein [90]
Gastric cancerIn vitro, in vivo Upregulation of caspase-3, -8 and -9 [91]
17CucurbitacinTriterpeneCucumis sativusC32H46O8558.7Colon cancerIn vitro Inhibition of Hippo-YAP Signaling Pathway [92]
Gastric cancerIn vitro, in vivo Suppression of Akt expression [93]
Bile duct cancerIn vitro Downregulation of pRB, cyclin D1 and cyclin E expression [94]
Breast cancerIn vitro Inhibition of Stat3 and Akt signaling [95]
18CurcuminCurcuminoidsCurcuma longaC21H20O6368.38Breast cancerIn vitro Upregulation of PTEN/Akt signaling pathway [96]
Gastric cancerIn vitro Suppression of PI3K/Akt/mTOR signaling pathway [49]
Oral cancerIn vivo Suppression of NF-κB, and COX-2 expression [97]
Prostate cancerIn vitro Downregulation of NF-κB, and CXCL1 and -2 expressions [98]
Colon cancerIn vitro Inhibition of AMPK-induced NF-κB, uPA, and MMP9 activation [99]
Ovarian cancerIn vitro JAK/STAT3 pathway inhibition [100]
Lung cancerIn vitro Increase in FOXA2 expression [101]
19DiosgeninSaponinDioscorea villosaC27H42O3414.6Breast cancerIn vitro Downregulation of Skp2 [102]
Liver cancerIn vitro Inhibition of Akt and upregulation of p21 and p27 expression [103]
20D-limoneneTerpeneCitrus aurantiumC10H16136.23Colon cancerIn vitroInactivation of Akt pathway [104]
Lung cancerIn vitroUpregulation of Atg5 [105]
Prostate cancerIn vitroGeneration of ROS, and activation of caspase-3 and -9 [106]
21Emodin ResinRheum palmatumC15H10O5270.24Breast cancerIn vitro Activation of AhR-CYP1A1 signaling pathway [107]
Lung cancerIn vitro Suppression of HAS2-HA-CD44/RHAMM pathway [108]
Pancreatic cancerIn vitro, in vivo Downregulation of NF-κB, VEGF, MMP-2, and -9 [109]
Colon cancerIn vitro Suppression of PI3K/AKT signaling [110]
Prostate cancerIn vitro Downregulation of VEGF [111]
22Epigallocatechin gallate (EGCG)CatechinCamellia sinensisC22H18O11458.4Bile duct cancerIn vitro, in vivo Suppression of Notch1, MMP-2, and -9 signaling [112]
Lung cancerIn vitro Activation of AMPK signaling pathway [113]
Ovarian cancerIn vitro Induce DNA damage [114]
Prostate cancerIn vitro, in vivo Inhibition of HSP90 function [115]
Head & neck cancerIn vitro, in vivo Inhibition of beta-catenin expression [116]
Colon cancerIn vitro Induction of ER stress through PERK/p-eIF2α/ATF4 and IRE1α pathways activation [117]
23ErianinBisbenzylDendrobium
chrysotoxum		C18H22O5318.4Breast cancerIn vitro Activation PI3K/Akt pathway [118]
Lung cancerIn vitro, in vivo Induction of Ca2+/CaM-dependent ferroptosis [119]
Liver cancerIn vitro, in vivo Induction of oxidative stress-mediated mitochondrial apoptosis [73]
Oral cancerIn vitro Regulation of MAPK pathway [120]
Bladder cancerIn vitro, in vivo Increase in p-JNK level and induce c-Jun and Bcl-2 phosphorylation [121]
Bone cancer In vitro, in vivo Activation of ROS/JNK signaling [122]
Colon cancerIn vitroActivation of JNK pathway [123]
Cervical cancerIn vitro Regulation of ERK1/2 signaling [124]
24EvodiamineAlkaloidEvodia rutaecarpaC19H17N3O303.4Lung cancerIn vitro, in vivo Elevation of CD8+ T cells and downregulation of MUC1-C/PD-L1 axis [125]
Thyroid cancerIn vitroThrough M phase cell cycle arrest and apoptosis’s induction [126]
Prostate cancerIn vitro Activation of caspase-3 and -9 [127]
Liver cancerIn vitro Deactivation of PI3K/AKT pathway [128]
Bladder cancerIn vitro Enhance activation of P38 and JNK signaling [129]
Colon cancerIn vitro, in vivo Inhibition of acetyl-NF-κB, p65 and MMP-9 expression [130]
Ovarian cancerIn vitro Elevation of p27 and p21, and inhibition of Cdc2 expression [131]
Pancreatic cancerIn vitro Inhibition of NF-κB, p65, and Bcl-2 expression, while activate Bax and cleaved caspase-3 [132]
25FlavopiridolFlavonoidsDysoxylum
binectariferum		C21H20ClNO541.8Breast cancerIn vitro Inhibition of cyclin-dependent kinases [133]
Thyroid cancerIn vitro, in vivo Reduction in Cyclin-dependent kinases (CDK) and MCL1 levels [134]
Bile duct cancerIn vitro, in vivo Suppression of cyclin-dependent kinase pathway [135]
Head & neck cancerIn vitro, in vivo Reduction in cyclin D1 expression [136]
Lung cancerIn vitro Reduction in E-cadherin level [137]
Esophageal cancerIn vitro, in vivo Decrease in c-Myc expression [138]
26Gallic AcidPhenolic acidGalanthus nivalisC7H6O5170.12Lung cancerIn vitro, in vivo Inhibition of PI3K/Akt pathway [139]
Liver cancerIn vitro Suppression of Wnt/β-catenin signaling [140]
Breast cancerIn vitro, in vivo Increases expression of cleaved caspase-7, -9, and p53, while reduces expression of Bcl-2, and PARP [141]
Colon cancerIn vitro, in vivoInhibition of SRC and EGFR phosphorylation [142]
Gastric cancerIn vitro Increases expression of caspase-3, -8, and P53 gene [143]
Prostate cancerIn vitro Generation of ROS [144]
Ovarian cancerIn vitro, in vivo Inhibition of carbonic anhydrase IX protein [145]
Pancreatic cancerIn vitro Downregulation of protein Bcl-,2 while increases in BAX expression [146]
27Gambogic acidResinGarcinia hanburyiC38H44O8628.7Lung cancerIn vitro, in vivo Downregulation of Bcl-2, and upregulation of Bax expression [147]
Breast cancerIn vitro, in vivo Increase the expression of Fas, cleaved caspase-3, -8, -9 and Bax proteins [148]
Liver cancerIn vitro Induces apoptosis through caspases 3, -7, -8 and -9 [149]
Prostate cancerIn vitro Induction of ROS production [150]
Colon cancerIn vitro, in vivo Inhibition of Akt-mTOR signaling [151]
Gastric cancerIn vitro, in vivo Downregulation of circ_ASAP2 and CDK7, while upregulation of miR-33a-5p expression [152]
28Genistein IsoflavonesGlycine maxC15H10O5270.24Liver cancerIn vitro Upregulation of Bax, cleaved caspase-3 and -9 and downregulation of Bcl-2 expression [153]
Colon cancerIn vitro, in vivo Suppression of MiR-95, Akt and SGK1 signaling [154]
Prostate cancerIn vitro, in vivo Decrease MMP-2 expression [155]
Lung cancerIn vitro Downregulation of FoxM1 [156]
29Gingerol PhenolZingiber officinaleC17H26O4294.4Breast cancerIn vitro Induction of p53-dependent intrinsic apoptosis [157]
Oral cancerIn vitro Activate caspases and increase Apaf-1 expression [158]
Cervical cancer
Lung cancerIn vitro, in vivo Reduction in ROS and iron accumulation and suppression of USP14 expression [159]
Pancreatic cancerIn vitro Inhibition of PI3K/AKT signaling [160]
30GinkgetinFlavonoidGinkgo bilobaC32H22O10566.5Breast cancerIn vitro Downregulation of estrogen receptor [161]
Lung cancerIn vitro, in vivoInhibition of p62/SQSTM1 signaling [162]
Prostate cancerIn vitro, in vivo Suppression of STAT3 expression [163]
Bone cancerIn vitro Inhibition of STAT3 and activation of caspase-3/9 [164]
Ovarian cancerIn vitro Induction of apoptosis by activation of caspase-3 [165]
Kidney cancerIn vitro Suppression of JAK2-STAT3 pathway [166]
31Glycyrrhizin TriterpenesGlycyrrhiza glabraC42H62O16822.9Breast cancerIn vitro, in vivo Induces ROS-mediated apoptosis [167]
Gastric cancerIn vitro Downregulation of PI3K/AKT pathway [168]
Prostate cancerIn vitro Induces DNA damage [169]
Ovarian cancerIn vitro Upregulation of Fas and FasL expression [170]
32GossypolPhenolGossypium
hirsutum		C30H30O8518.6Colon cancerIn vitro Suppression of genes coding expression for CLAUDIN1, FAS, IL2, and IL8 [171]
Breast cancerIn vitro Suppression of IKBKE, CCL2 and MAPK1 expression [172]
Lung cancerIn vitro Decrease EGFR phosphorylation and AKT/ERK signaling [173]
Prostate cancerIn vitro Activation of p53 protein [174]
Ovarian cancerIn vitroCause changes in thiol/redox states of proteins associated with glycolysis and stress responses [175]
Cervical cancerIn vitro, in vivo Inhibition of FAK signaling and reversing TGF-β1-induced EMT [176]
Head & neck cancerIn vivo Inhibition of Bcl-XL expression [177]
Skin cancerIn vitro Induces mitochondria-dependent apoptosis [178]
33HarmineAlkaloid Peganum
harmala		C13H12N2O212.25Breast cancerIn vitro, in vivoDownregulation of TAZ [179]
Thyroid cancerIn vitro, in vivoDownregulation of Bcl-2 and upregulation of Bax expression [180]
Gastric cancerIn vitro Inhibition of Akt/mTOR/p70S6K signaling [181]
Pancreatic cancerIn vitroSuppression of AKT/mTOR pathway [182]
Ovarian cancerIn vitroInhibition of ERK/CREB pathway [183]
Lung cancerIn vitro Suppression of AKT phosphorylation and enhances ROS generation [184]
34HesperidinFlavonoidCitrus limonC28H34O15610.6Lung cancerIn vitroDownregulation of FGF and NF-κB signal transduction pathways [185]
Gastric cancerIn vitro Increase in ROS levels and regulation of MAPK signaling [135]
Liver cancerIn vitro Downregulation of Bcl-xL and upregulation of Bax, Bak, and tBid proteins [186]
Skin cancerIn vitro Induces DNA damage [187]
Prostate cancerIn vitro Induces apoptosis triggered by ROS generation [188]
Breast cancerIn vitro Inhibition of PD-L1 expression via downregulation of Akt and NF-κB signaling [189]
35Hispidulin FlavoneSalvia involucrateC16H12O6300.26Lung cancerIn vitro, in vivo Induces ROS-mediated apoptosis via ER stress pathway [190]
Liver cancerIn vitro, in vivoUpregulation of PPARγ signaling [191]
Kidney cancerIn vitro, in vivoActivation of ROS/JNK signaling [192]
Gastric cancerIn vitro Activate ERK1/2 and NAG-1 signaling [193]
36KaempferolFlavonoidSpinacia oleraceaC15H10O6286.24Breast cancerIn vitroIncrease expression of H2AX, caspase-3, and -9 [194]
Liver cancerIn vitroActivation of AMPK signaling [195]
Kidney cancerIn vitroDownregulation of AKT and FAK pathways [196]
Cervical cancerIn vitroDisruption of mitochondrial membrane potential and intracellular free Ca2+ concentration [197]
Pancreatic cancerIn vitroInhibition of TGM2 expression [198]
Colon cancerIn vitroActivation of ATM and p53-Bax axis [199]
37KurarinoneFlavonoidSophora
flavescens		C26H30O6438.5Lung cancerIn vitro, in vivo Suppression of caspase-7 and -12, and AKT pathway [200]
Gastric cancerIn vitroInhibition of STAT3 signaling [201]
Breast cancerIn vitroInhibition of NF-κB activation [202]
38LappaconitineDiterpenoidAconitum
sinomontanum		 C32H44N2O8 584.7Colon cancerIn vitroDownregulation of PI3K/AKT/GSK3β signaling [203]
Lung cancerIn vitroDownregulation of Cyclin E1 expression [204]
Liver cancer In vitroUpregulation of Bax, P53, and downregulation of Bcl-2 expressions [205]
39Licochalcone AChalconeGlycyrrhiza glabraC21H22O4338.4Breast cancerIn vitroInhibition of PI3K/Akt/mTOR pathway [206]
Bladder cancerIn vitroInduces ER stress-dependent apoptosis caused by activation of ER-specific caspase-12 [207]
Lung cancerIn vitroInduces ERK and p38 activation while suppresses JNK signaling [208]
Liver cancerIn vitroDownregulation of MKK4/JNK [209]
40LiriodenineAlkaloidEnicosanthellum pulchrumC17H9NO3275.26Breast cancerIn vitroUpregulation of p53 [210]
Lung cancerIn vitroLockage of cell cycle progression at the G2/M phase [211]
Ovarian cancerIn vitroInhibition of progression of CAOV-3 cell cycle in S phase [212]
41LuteolinFlavonoidReseda luteolaC15H10O6286.24Liver cancerIn vitroIncreases caspase-8 and decreases Bcl-2 expression [213]
Colon cancerIn vitroUpregulation of Nrf2 expression [214]
Gastric cancerIn vitroInhibition of STAT3 phosphorylation [215]
Oral cancerIn vitroSuppression of EMT-induced transcription factors [216]
Breast cancerIn vitroSuppression of NF-κB/c-Myc activation and hTERT transcription [217]
Pancreatic cancerIn vitroInhibition of VEGF expression [218]
Lung cancerIn vitroInhibition of FAK-Src signaling [219]
42LycopeneCarotenoid Solanum
lycopersicum		C40H56 536.9Breast cancerIn vitro Inhibition of Akt phosphorylation [220]
Prostate cancerIn vitro, in vivo Downregulation of IL1, IL6, IL8, and TNF-α levels [221]
Colon cancerIn vitro Suppression of NF-κB and JNK signaling [222]
Pancreatic cancerIn vitroInhibition of ROS-Mediated NF-κB Signaling [223]
Lung cancerIn vitro, in vivoInduction of RARβ expression [224]
Gastric cancerIn vivo Increase in SOD, and CAT, while decrease in MDA levels [225]
Cervical cancerIn vitro Upregulation of Bax, and downregulation of Bcl-2 expression [226]
Skin cancerIn vivo Inhibition of PCNA expression [227]
Brain cancerIn vitro Activation of caspase-3 pathway [228]
Ovarian cancerIn vitro, in vivoDecrease in integrin α5 expression and MAPK activation [229]
43LycorineAlkaloidCrinum asiaticumC16H17NO4287.31Breast cancerIn vitro, in vivoInhibition of STAT3 signaling pathway [230]
Gastric cancerIn vitro, in vivoEnhances FBXW7-MCL1 axis level [224]
Prostate cancerIn vitro, in vivoInhibition of JAK/STAT signaling [231]
Lung cancerIn vitro, in vivoInhibition of Wnt/β-catenin signaling [232]
Liver cancerIn vitro inhibition of ROCK1/cofilin-induced actin dynamics [233]
44MagnololLignanMagnolia officinalisC18H18O2 266.3Lung cancerIn vitro, in vivoDownregulation of Akt/mTOR pathway [234]
Gallbladder cancerIn vitro, in vivoIncrease in p53 expression [235]
Liver cancer In vitroInhibition of ERK-modulated metastatic process [236]
Prostate cancerIn vitroDownregulation of MMP-2 and MMP-9 expression [237]
Esophageal cancerIn vitroActivation of MAPK pathway [238]
45MatrineAlkaloidSophora flavescensC15H24N2O248.36Prostate cancerIn vitro Enhances expression of GADD45B, tumor suppresser gene or AKT/GSK3β/β-catenin [239]
Ovarian cancerIn vitro, in vivoSuppression of PI3K/AKT/mTOR pathway expression [240]
Colon cancerIn vitro Upregulation of Bax, downregulation of Bcl-2, and activation of caspase-3 and -9 [241]
Liver cancerIn vitro, in vivoUpregulation of miR-345-5p and downregulation of circ_0027345 and HOXD3 [242]
Lung cancerIn vitro Downregulation of C-C chemokine receptor type 7 (CCR7) [243]
46MyricetinFlavonoidMyrica nagi ThunbC15H10O8318.23Thyroid cancerIn vitro DNA damaging and inducing the release of apoptosis-inducing factor (AIF) [244]
Bladder cancerIn vitro, in vivo Activation of caspase-3, and inhibition of Akt and MMP-9 expression [245]
Colon cancerIn vitro Increases BAX/BCL2 ratio and AIF release [246]
Prostate cancerIn vitro Inhibition of PIM1 and disruption of PIM1/CXCR4 interaction [247]
Breast cancerIn vitro Enhances intracellular ROS production [248]
Lung cancerIn vitro Inhibition of FAK-ERK signaling pathway [249]
47NimbolideLimonoid
triterpene		Azadirachta indica C27H30O7466.5Pancreatic cancerIn vitro, in vivoReduction in PI3K/AKT/mTOR and ERK signaling [250]
Colon cancerIn vitro, in vivoInhibition of Bcl-x, CXCR4, VEGF, and NF-κB [251]
Bladder cancerIn vitro Stimulation of p38 MAPK and AKT phosphorylation [252]
48NoscapineAlkaloidPapaver
somniferum		C22H23NO7413.4Colon cancerIn vitro Inhibition of PI3K/AKT/mTOR pathway [253]
Breast cancerIn vitro Decreases NF-κB and increases IκBα expression [254]
Lung cancerIn vitro, in vivoUpregulation of PARP, Bax, and repression of Bcl2 expression [255]
Prostate cancerIn vivo Suppression of microtubule dynamics [256]
49OridoninDiterpenoidRabdosia rubescensC20H28O6364.4Colon cancerIn vitro, in vivo Downregulation of GLUT1 and induction of autophagy [257]
Liver cancerIn vitro, in vivoInhibition of Akt pathway [258]
Ovarian cancerIn vitro Suppression of mTOR pathway [259]
Bladder cancerIn vitro, in vivoInactivation of ERK and AKT signaling pathways [260]
Esophageal cancerIn vitro, in vivoSuppression of AKT signaling [261]
Breast cancerIn vitro Decrease in expression of MMPs and regulation of Integrin β1/FAK pathway [262]
Bone cancerIn vitro, in vivoActivation of PPAR-γ and inhibition of Nrf2 pathways [263]
50OxymatrineAlkaloidSophora flavescensC15H24N2O2264.36Cervical cancerIn vitro Suppression of AKT/mTOR [264]
Breast cancerIn vitro Suppress the PI3K/Akt [265]
Pancreatic cancerIon vitroDownregulation of Livin and Survivin expression and upregulation of Bax/Bcl-2 ratio [266]
Prostate cancerIn vitro, in vivoIncrease in expression of p53 and Bax, and decrease in Bcl-2 level [267]
51Physapubescin B SteroidPhysalis pubescensC30H42O8530.6Ovarian cancerIn vitro Suppress transcriptional activity of STAT3 [268]
Kidney cancerIn vitro, in vivo Decreases expression of HIF-2α and activation of caspase-3 and -8 [269]
52PinostrobinFlavonoidBoesenbergia
rotunda		C16H14O4270.28Cervical cancerIn vitroIncreases expressions of TRAIL, FADD and production of ROS [270]
Breast cancerIn vitroDownregulation of FAK and RhoA signaling [271]
Lung cancerIn vitroVia promoting apoptosis [272]
Prostate cancerIn vitroDecrease in cyclins B expression [273]
53PiperineAlkaloidPiper nigrumC17H19NO3285.34Colon cancerIn vitroSuppression of Wnt/β-catenin pathway [274]
Lung cancerIn vitroInduces p53-mediated cell cycle arrest and apoptosis via activation of caspase-3 and -9 cascades [275]
Breast cancerIn vitro, in vivoInduction of cell apoptosis and cell cycle blockage [276]
Prostate cancerIn vitro Downregulation of cyclin A & D1 [277]
54PiperlongumineAlkaloidPiper longumC17H19NO5317.34Lung cancerIn vitroInhibition of Akt phosphorylation [278]
Prostate cancerIn vitroInduces DNA damage [279]
Colon cancerIn vitroInduces DNA damage via increasing ROS production [280]
55PlumbaginAlkaloidPlumbago zeylinicaC11H8O3 188.18Breast cancerIn vitro Upregulation of p53 and p21 [281]
Colon cancerIn vitro Induction of ROS formation [282]
Liver cancerIn vitro, in vivo Downregulation of SIVA/mTOR signaling [283]
Prostate cancerIn vitro, in vivoInduction of ROS production, and activation of ER stress [284]
Lung cancerIn vitro Activation of caspase-9 and ROS production [285]
Esophageal cancerIn vitro, in vivo Inhibition of STAT3-PLK1-AKT signaling [286]
Bone cancerIn vitro Downregulation of c-Myc expression [287]
Cervical cancerIn vitro Downregulation of MMP 2, 9, β-catenin and N-cadherin, while upregulation of E-cadherin signaling [288]
56PristimerinTriterpenoidMortonia greggiiC30H40O4464.6Colon cancerIn vitroDecreases in AKT expression [289]
Oral cancerIn vitroInhibition of MAPK/Erk1/2 and Akt signaling [290]
Prostate cancerIn vitroInhibition of HIF-1α [291]
Lung cancerIn vitroDownregulation of integrin β1 and MMP2 expression [292]
Pancreatic cancerIn vitroInhibition of Akt/NF-κB/mTOR signaling [293]
57Pterostilbene StilbenoidPolygonum
cuspidatum		C16H16O3256.3Ovarian cancerIn vitro Decreases release of NF-κB p50, and NF-κB p65 [294]
Lung cancerIn vitro, in vivo Enhance ROS generation, caspase-3 activity and ER stress [295]
Breast cancerIn vitro Inactivate AKT and mTOR signaling pathways [296]
Colon cancerIn vitro, in vivo Facilitate DNA repairing mediated through Top1/Tdp1 pathway [297]
58PuerarinIsoflavonePueraria radixC21H20O9416.4Colon cancerIn vitro Increase Bax expression and caspase-3 activation [298]
Prostate cancerIn vitroInhibition of Keap1/Nrf2/ARE signaling pathways [299]
Lung cancerIn vitro, in vivo Inhibition of PI3K/Akt pathway [300]
Liver cancerIn vitro Modulation of MAPK signaling pathway [301]
Brain cancerIn vitro Suppression of p-Akt and Bcl-2, while enhancement of Bax and cleaved caspase-3 expression [302]
59QuercetinFlavonoidAllium cepaC15H10O7302.23Thyroid cancerIn vitro Upregulation of Pro-NAG-1/GDF15 [303]
Breast cancerIn vitro Inactivation of caspase-3 pathway [304]
Liver cancerIn vitroInhibition of PI3K/Akt and ERK pathways [305]
Prostate cancerIn vitroEnhances release of tumor suppressor genes i.e., PTEN, p53 and TSC [306]
Lung cancer In vitroInhibition of NF-κB Signaling [307]
60ResveratrolStilbenoidPolygonum
cuspidatum		C14H12O3228.24Colon cancerIn vitro Inactivates PI3K/Akt signaling [308]
Breast cancerIn vitroSuppression of Integrin αvβ3 expression [309]
Ovarian cancerIn vitro Inactivation of STAT3 signaling [310]
Pancreatic cancerIn vitro Suppression of NAF-1 expression, induces ROS
accumulation, and activation of Nrf2 signaling [311]
Gastric cancerIn vitro Upregulation of Bax, cleaved caspase-3 and -8 while suppression of NF-κB activation [312]
Lung cancerIn vitro, in vivo Decreases SIRT1-mediated NF-κB activation [313]
Skin cancerIn vitro, in vivoDeacetylation of SIRT1-activated NF-κB [314]
61RutinFlavonoidRuta graveolensC27H30O16610.5Colon cancerIn vitro Inhibition of caspase-3 expression [315]
Brain cancerIn vitro Upregulation of P53 expression [265]
Skin cancerIn vitro Suppression of PI3K/Akt and Wnt/β-catenin signaling [316]
Breast cancerIn vitro, in vivo Inhibition of tyrosine kinase c-Met receptor [317]
62SafranalAlkaloidCrocus sativusC10H14O150.22Colon cancerIn vitro Suppression of PI3K/Akt/ mTOR pathway [318]
Liver cancerIn vitro Activation of caspases-8 and -9 [319]
Prostate cancerIn vitro, in vivo Downregulation of AKT and NF-κB signaling [320]
Breast cancerIn vitro Inhibits DNA and RNA synthesis [321]
63ShikoninQuinoneLithospermum erythrorhizonC16H16O5 288.29Lung cancerIn vitro Downregulation of PFKFB2 expression [322]
Colon cancerIn vitro Reduction in peroxiredoxin V (PrxV) expression [323]
Prostate cancerIn vitro Induces necroptosis by decreasing caspase-8 and increasing pRIP1 and pRIP3 [324]
Liver cancerIn vitro, in vivo Inhibition of PKM2 expression [325]
Ovarian cancer In vitro Decreases Bcl-2 expression and increases BAX, caspase-3 and -9 expression [326]
Skin cancerIn vitro, in vivo Inhibition of MAPK pathway-mediated induction of apoptosis [327]
Bile duct cancerIn vitro Inhibitions of PKM2 expression [328]
Breast cancerIn vitro Inhibition of epidermal growth factor receptor signaling [329]
64ShogaolPhenolZingiber officinaleC17H24O3276.4Breast cancerIn vitro Inhibition Akt and STAT signaling pathway [330]
Prostate cancerIn vitro, in vivo Inhibition of STAT3 and NF-κB signaling [331]
Lung cancerIn vitro, in vivo Inhibits secretion of CCL2 [332]
Cervical cancerIn vitro Induces apoptosis and G2/M cell cycle arrest [333]
65SilibininFlavonolignanSilybum marianumC25H22O10 482.4Breast cancerIn vivo Inhibition of EGF–EGFR signaling pathway [334]
Lung cancerIn vitro, in vivo Activation of EGFR/LOX pathway [335]
Ovarian cancer In vitro, in vivoInhibition of ERK and Akt pathway [336]
Prostate cancerIn vitro Suppression of vimentin and MMP-2 expression [337]
Skin cancerIn vivo Via Pro-Oxidant activity [338]
Colon cancerIn vitro Downregulation of COX-2, VEGF, MMP-2, & -9, and CXCR-4 expression [339]
Gastric cancerIn vitro Inhibition of STAT3 pathway [340]
66SilymarinFlavonolignanSilybum marianumC25H22O10482.4Oral cancerIn vitro, in vivo Induction of DR5/caspase-8 apoptotic signaling [289]
Gastric cancerIn vitro Inhibition of p-ERK and activation of p-p38 and p-JNK pathways [341]
Colon cancerIn vitro Increases ATF3 transcription through activation of JNK and IκK-α [291]
Prostate cancerIn vitro Inhibition of cyclins (A, B1, D, E) and cyclin-dependent kinase pathway [337]
Breast cancerIn vitro, in vivo Regulation of MAPK signaling pathway [342]
Liver cancerIn vivoReduction in ROS levels [343]
67SolamargineAlkaloidSolanum nigrum L.C45H73NO15 868.1Gastric cancerIn vitro, in vivo Inhibition of Erk1/2 MAPK phosphorylation [344]
Skin cancerIn vitro Downregulation of hILP/XIAP [345]
Bone cancerIn vitroSuppression of notch pathway [346]
Liver cancerIn vitroInduction of apoptosis [347]
Prostate cancerIn vitro, in vivoSuppression of MUC1 expression [348]
68StachydrineAlkaloidHerba LeonuriC7H13NO2143.18Breast cancerIn vitroInhibition of Akt/ERK pathways [349]
Prostate cancerIn vitroInhibits CXCR3 and CXCR4 expressions [350]
69SugiolDiterpeneSalvia prionitisC20H28O2300.4Ovarian cancerIn vitroBlockage of RAF/MEK/ERK signaling pathway [351]
Prostate cancerIn vitro, in vivoInhibits STAT3 activity and increase ROS level [352]
Pancreatic cancerIn vitro Induces ROS-mediated alterations in MMP [353]
Uterine cancerIn vitro Increases Bax and decreases Bcl-2 expressions [354]
70TanshinoneTerpenoidsSalvia miltiorrhizaC18H12O3 276.3Lung cancerIn vitro, in vivo Suppression of IL-8 through NF-κB and AP-1
Pathways [355]
Gastric cancerIn vitro, in vivoDownregulation of STAT3 pathway [356]
Breast cancerIn vitro Suppression of HIF-1α and VEGF [357]
Ovarian cancerIn vitro, in vivoDownregulation of Bcl-2, VEGF, COX2 and upregulation of Bax expressions [358]
Bladder cancerIn vitro Activation of caspases 3 and -9 [359]
Cervical cancerIn vitro Decrease in Bcl-2, HPV 16 and E7 protein levels, while increase in Bax and caspase-3 expressions [360]
71TectochrysinFlavonoidsAlpinia oxyphyllaC16H12O4 268.26Colon cancerIn vitroInhibition of NF-κB signaling [361]
Prostate cancerIn vitroSuppression of PI3K/AKT pathway [362]
Lung cancerIn vitroInhibition of STAT3 signaling [363]
72TetrandrineAlkaloidStephania tetrandraC38H42N2O6622.7Cervical cancerIn vitro, in vivoDownregulation of MMP2 and MMP9 [364]
Breast cancer In vivo Upregulation of Caspase-3, Bax, and downregulation of Bcl-2, Survivin, and PARP signaling [365]
Gastric cancerIn vitro, in vivoActivation of caspase-3 and -9, and upregulation of apaf-1 [366]
Colon cancerIn vitroInhibition of EMT transition [367]
Prostate cancerIn vitro Induction of DR4 and DR5 expression, and TRAIL-mediated apoptosis [368]
Bone cancerIn vitro, in vivoInhibition of PTEN/Akt, MAPK/Erk and Wnt signaling pathways [369]
73Thymol PhenolThymus vulgarisC10H14O 150.22Lung cancer In vitroEnhances cytoplasmic membrane permeability and cell apoptosis [370]
Breast cancer
Prostate cancer
Colon cancerIn vitroSuppression of Wnt/β-Catenin pathway [371]
Gastric cancerIn vitroActivation of Bax, PARP, and caspase-8 proteins [372]
74Thymoquinone QuinoneNigella sativaC10H12O2164.2Kidney cancerIn vitro Inhibition of AKT phosphorylation [373]
Breast cancerIn vitro, in vivo Through phosphorylation of p38 via ROS generation [374]
Bladder cancerIn vitro Inhibition of mTOR signaling [375]
Colon cancerIn vitroInhibition of STAT3, JAK2- and EGF receptor
tyrosine kinase [376]
Gastric cancerIn vitro, in vivo Inhibition of STAT3 pathway [377]
Liver cancer In vitro Inhibition of IL-8 expression, and activation of TRAIL receptors [378]
Lung cancerIn vitro Reduction in ERK1/2 phosphorylation [379]
Oral cancerIn vitro Downregulation of p38β MAPK [380]
Pancreatic cancerIn vitro Downregulation of mucin 4 expression [381]
75Ursolic acid TriterpenoidsOldenlandia diffusaC30H48O3 456.7Ovarian cancerIn vitro Downregulation of PI3K/AKT pathway [382]
Lung cancerIn vitro Enhances apoptosis-inducing factor (AIF) and endonuclease G release [383]
Colon cancerIn vitro, in vivo Inhibition of IL-6-mediated STAT3 pathway [384]
Breast cancerIn vitro Downregulation of Nrf2 expression [385]
Pancreatic cancerIn vitro, in vivo Inhibition of NF-κB and STAT3 pathways [386]
Gallbladder cancerIn vitroActivation of caspase-3, -9 and PARP pathway [387]
76Withaferin-A steroidal
lactone		Withania somniferaC28H38O6470.6Breast cancerIn vitro Inhibition of TASK-3 expression [388]
Oral cancerIn vitro Upregulation of Bim and Bax expression [389]
Skin cancerIn vitro Activation of TRIM16 [390]
Bone cancerIn vitroInactivation of Notch-1 signaling [391]
Colon cancerIn vitro, in vivoInhibition of STAT3 Transcriptional activity [392]
77WogoninFlavonoidScutellaria
baicalensis		C16H12O5284.26Colon cancerIn vitroIncreases ER stress, and mediates p53 phosphorylation [393]
Cervical cancerIn vitroInhibition of Cdk4 and cyclin D1 [394]
Lung cancerIn vitroDownregulation of SGK1 protein levels [395]
Bone cancerIn vitroIncreases ROS level [396]
Breast cancerIn vitroActivation of ERK and p38 MAPKs pathways [397]
Ovarian cancerIn vitroIncrease in p53 and decrease in VEGF proteins expression [398]
78XanthatinSesquiterpene lactoneXanthium
strumarium		C15H18O3246.3Skin cancerIn vitro, in vivo Inhibition of Wnt/β-catenin pathway [399]
Lung cancerIn vitro, in vivoInhibition of GSK-3β signaling [400]
Breast cancerIn vitro, in vivoInhibition of VEGFR2 signaling [401]
Colon cancerIn vitro Inhibition of mTOR pathway [402]
Table
Table 3. Number of effective phytochemicals against different types of cancer.
Table 3. Number of effective phytochemicals against different types of cancer.
Cancer TypeNumber of
Phytochemicals		Cancer TypeNumber of
Phytochemicals		Cancer TypeNumber of
Phytochemicals
Breast cancer55Pancreatic cancer18Esophageal cancer6
Colon cancer53Cervical cancer14Thyroid Cancer6
Lung cancer53Bladder cancer13Bile duct cancer5
Prostate cancer45Bladder cancer13Brain cancer5
Liver cancer30Skin cancer11Miscellaneous10
Ovarian Cancer27Oral cancer9NANA
Gastric cancer24Kidney cancer7NANA
Table
Table 4. Phytochemicals with activity against different number of cancer types.
Table 4. Phytochemicals with activity against different number of cancer types.
Sr #PhytochemicalsEffective against Number of Cancer Types
1Lycopene10
2Baicalin, Corosolic acid, Plumbagin, Shikonin, Thymoquinone 9
3Erianin, Evodiamine, Gallic acid, Gossypol8
4Apigenin, Curcumin, Luteolin, Oridonin, Resveratrol, Silibinin7
5Other phytochemicals≤6
Table
Table 5. List of phytochemicals approved by the FDA or in clinical trials for various types of cancer.
Table 5. List of phytochemicals approved by the FDA or in clinical trials for various types of cancer.
Sr #PhytochemicalsSourceCancer TypeDevelopment StageStatusTrade NameNCT Number
1VincristineCatharanthus roseusAcute leukemiaFDA approved1963OncovinNA
2PaclitaxelTaxus braciolaLate-stage pancreatic cancerFDA approved2013Abraxane®NA
Advanced non-small cell lung cancerFDA approved2012Abraxane®NA
Metastatic breast cancerFDA approved2005Abraxane®NA
3CurcuminCurcuma longaProstate cancerPhase 3Recruiting,
15 June 2021		Biocurcumax (BCM-95) ®NCT03769766
Cervical cancerPhase 2Not yet recruiting,
25 June 2021		Curcugreen (BCM-95) ®NCT04294836
Pancreatic cancerPhase 2Recruiting, 2020NANCT00094445
Gastric cancerPhase 2Not yet recruiting,
13 January 2022		Meriva®NCT02782949
Breast cancerPhase 1Recruiting,
23 February 2021		NA NCT03980509
4LycopeneSolanum lycopersicumProstate cancerPhase 3Completed,
23 January 2018		NA NCT01105338
5ResveratrolPolygonum
cuspidatum		Multiple myeloma cancerPhase 2Terminated (collecting more data) 27 February 2019SRT501NCT00920556
Colon cancerPhase 1Completed, 14 June 2017SRT501NCT00920803
Neuroendocrine cancerNACompleted, 18 November 2019NANCT01476592
6CapsaicinCapsicum annuumBreast cancerPhase 3Recruiting,
29 December 2021		Qutenza®NCT03794388
Head and neck cancerPhase 2Recruiting,
5 August 2021		Qutenza®NCT04704453
Prostate cancerPhase 2Not yet recruiting,
16 January 2014		CayenneNCT02037464
7Chlorogenic acidEtlingera elatiorLung cancerPhase 2Recruiting,
26 November 2018		NA NCT03751592
8ColchicineColchicum autumnaleLiver cancerPhase 2Recruiting, 11 February 2020ColchicineNCT04264260
9GenisteinGlycine maxProstate cancerPhase 2Temporarily
suspended,
4 December 2020		NA NCT02766478
Colorectal cancerPhase 2Completed,
10 May 2019		BonisteinNCT01985763
Prostate cancerPhase 2Completed,
6 August 2019		Novasoy 400NCT01036321
Bladder cancerPhase 2Completed,
10 June 2021		NA NCT00118040
10CamptothecinCamptotheca acuminataSolid tumorPhase 2Completed,
28 May 2020		CRLX101NCT00333502
Stomach and esophageal cancerPhase 2Completed,
1 February 2018		CRLX101NCT01612546
Advanced non-small cell lung cancerPhase 2Completed,
28 May 2020		CRLX101NCT01380769
11PiperinePiper nigrumProstate cancerPhase 2Not yet recruiting,
3 November 2021		NA NCT04731844
12SilibininSilybum marianumProstate cancerPhase 2Completed,
31 March 2014		Silibin-PhytosomeNCT00487721
13QuercetinAllium cepaSquamous cell carcinomaPhase 2Recruiting,
28 October 2021		NA NCT03476330
14 Epigallocatechin
gallate		Camellia sinensisColon cancerPhase 1Recruiting,
15 December 2021		Teavigo™NCT02891538
Esophageal cancerPhase 1Recruiting,
10 September 2021		NA NCT05039983
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Khan, A.W.; Farooq, M.; Haseeb, M.; Choi, S. Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action. Cells 2022, 11, 1326. https://doi.org/10.3390/cells11081326

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Khan AW, Farooq M, Haseeb M, Choi S. Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action. Cells. 2022; 11(8):1326. https://doi.org/10.3390/cells11081326

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Khan, Abdul Waheed, Mariya Farooq, Muhammad Haseeb, and Sangdun Choi. 2022. "Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action" Cells 11, no. 8: 1326. https://doi.org/10.3390/cells11081326

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