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

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.

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
Italy	686.8	13	289.0	15
North America	693.2	–	189.6	–
USA	689.3	12	185.0	54
Canada	726.9	7	229.7	33
South America	224.8	–	109.1	–
Brazil	278.6	63	122.3	72
Argentina	289.6	60	155.0	63
Colombia	222.5	75	108.1	81
Africa	82.7	–	53.1	–
South Africa	182.4	83	95.8	87
Morocco	160.8	93	95.5	88
Ethiopia	67.3	158	45.1	155
Australia	784.4	2	189.2	51
New Zealand	745.2	5	217.9	38

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.

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.

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.

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.

Table 2

Plant-derived phytochemicals with potential anticancer properties, and their mechanisms of action.

Sr #	Phytochemicals	Chemical Nature	Plant’s Source/Origin	Chemical Structure	M: Weight (g/mol)	Cancer Type	Study Type	Targets and Mechanisms
1	Allicin	Thioester	Allium sativum	C6H10OS2	162.3	Lung cancer	In vitro	Downregulation of VEGF expression [12]
						Gastric cancer	In vitro	Enhanced expression of p38 and cleavage caspase-3 [13]
						Oral cancer	In vitro	Upregulation of and cleaved caspase-3 [14]
						Brain cancer	In vitro	Elevation in Fas/FasL expression [15]
2	Aloperine	Alkaloid	Sophora alopecuroides	C15H24N2	232.36	Ovarian cancer	In vitro	Reactive oxygen species activation [16]
						Thyroid cancer	In vitro	Suppression of Akt pathway and downstream B-cell lymphoma (Bcl-2) expression [17]
						Prostate cancer	In vitro, in vivo	Inhibition of Akt and ERK phosphorylation [18]
						Bladder cancer	In vitro	Downregulation of Ras, p-Raf1 and p-Erk1/2 expression [19]
						Colon cancer	In vitro	Inhibition of JAK/Stat3 and PI3K/Akt pathways [20]
						Bones cancer	In vitro	Suppression of PI3K/AKT signaling [21]
3	Alpinumisoflavone	Isoflavone	Derris eriocarpa	C20H16O5	336.3	Colon cancer	In vitro	Blockage of DNA repairing [22]
						Esophageal cancer	In vitro, in vivo, ex-vivo	Upregulation of miR-370 and suppression of PIM1 signaling [23]
						Brain cancer	In vitro	Suppression of glycolysis and cyclin D1 expression and activation of caspase-9 [24]
4	Amygdalin	Diglucoside	Rosaceae kernels	C20H27NO11	457.4	Bladder cancer	In vitro	Modulation of β1 or β4 integrin expression [25]
						Breast cancer	In vitro	Downregulation of Bcl-2, upregulation of Bax and p38 MAPK signaling pathways [26]
						Prostate cancer	In vitro	Activation of caspase-3 through downregulation of Bcl-2 and up-regulation of Bax [27]
						Cervical cancer	In vitro	Downregulation of Bcl-2 and upregulation of Bax protein [28]
5	Andrographolide	Diterpenoid	Andrographis paniculata	C20H30O5	350.4	Colon cancer	In vitro	Increase intracellular ROS level [29]
						Skin cancer	In vitro	Activation of JNK and p38 signaling pathway [30]
						Breast cancer	In vitro, in vivo	Suppressing of COX-2 and VEGF pathway [31]
						Prostate cancer	In vitro, in vivo	Facilitate DNA damage [32]
						Bile duct cancer	In vitro	Suppression of Claudin-1 via p-38 pathway [33]
						Ovarian cancer	In vitro	Upregulation of TIMP1 expression [34]
6	Apigenin	Flavonoid	Matricaria chamomilla	C15H10O5	270.24	Colon cancer	In vitro, in vivo	Inhibition of the Mcl-1, AKT, and ERK pro-survival regulators [35]
						Lung cancer	In vitro, in vivo	Inhibition of NF-κB, AKT and ERK pathway [36]
						Liver cancer	In vitro, in vivo	Inhibition of PI3K/Akt/mTOR signaling [37]
						Pancreatic cancer	In vitro	Through G2/M cell cycle arrest [38]
						Breast cancer	In vitro	Inhibition of YAP/TAZ activity [39]
						Prostate cancer	In vitro, in vivo	Suppression of NF-κB/p65 expression [40]
						Bone cancer	In vitro	Suppression of Wnt/β-catenin signaling [41]
7	Artemisinin	Alkaloid	Artemisia annua	C15H22O5	282.33	Colon cancer	In vitro and in vivo	Increase in ROS production [42]
						Kidney cancer	In vitro, in vivo	Inhibition of AKT signaling [43]
						Ovarian cancer	In vitro, in vivo	Suppression of AKT/ERK/mTOR pathway [44]
						Gallbladder cancer	In vitro, in vivo	Inhibition of ERK1/2 pathway [45]
8	Baicalein	Flavonoid	Scutellaria baicalensis	C15H10O5	270.24	Lung cancer	In vitro, in vivo	Suppression of VEGF, FGFR-2, and RB-1 pathways [46]
						Colon cancer	In vitro	Activation of caspase-3 [47]
						Bladder cancer	In vitro, in vivo	Inhibition of cyclin B1, MMP-2 and MMP-9 mRNA expressions [48]
						Pancreatic cancer	In vitro, in vivo	Increase caspase-3 and Bax, while decrease survivin and Bcl-2 expressions [49]
						Liver cancer	In vitro	Suppression of PI3K/Akt pathway [50]
						Prostate cancer	In vitro	Inhibition of caveolin-1/AKT/mTOR pathway [51]
						Breast cancer	In vitro, in vivo	Activation of PAX8-AS1-N activation [52]
						Ovarian cancer	In vitro, in vivo	Inhibition of YAP and RASSF6 expressions [53]
						Skin cancer	In vitro, in vivo	Inhibition of glucose uptake and metabolism of tumor cells [54]
9	Berbamine	Alkaloid	Berberis amurensis	C37H40N2O6	608.7	Blood cancer	In vitro	Upregulation of caspase-3 and downregulation of MDR-1 gene expression [55]
						Liver cancer	In vitro, in vivo, ex vivo	Inhibition of Ca2+/Calmodulin-dependent protein Kinase II expression [56]
						Ovarian cancer	In vitro, in vivo	Inhibition of Wnt/β-catenin signaling [57]
						Colon cancer	In vitro	Inhibition of MEK/ERK signaling [58]
						Head & neck cancer	In vitro	Inhibition of STAT3 activation [59]
10	Capsaicin	Capsaicinoid	Capsicum annuum	C18H27NO3	305.4	Breast cancer	In vitro, in vivo	Downregulation of FBI-1-mediated NF-κB pathway [60]
						Lung cancer	In vivo	Downregulation of MMP-2 and -9 levels [61]
						Prostate cancer	In vitro	Increases protein light chain 3-II (autophagy marker) and ROS levels [62]
						Colon cancer	In vitro	Stabilization and activation of p53 [63]
						Esophageal cancer	In vitro	Decrease hexokinase-2 (HK-2) expression [64]
						Skin cancer	In vitro	Downregulation of PI3-K/Akt/Rac1 pathway [65]
11	Cepharanthine	Alkaloid	Stephania cepharantha	C37H38N2O6	606.7	Colon cancer	In vitro	Upregulation of p21Waf1/Cip1 pathway [66]
						Breast cancer	In vitro	Inhibition of AKT/mTOR signaling [67]
						Ovarian cancer	In vitro	Increases expression of p21Waf1 and decreasing expression of cyclins A and D proteins [68]
						Liver cancer	In vitro	Activation of JNK1/2 signaling and downregulation of Akt pathway [69]
12	Chlorogenic Acid	Ester	Etlingera elatior	C16H18O9	354.31	Liver cancer	In vitro, in vivo	Inhibition of DNMT1 expression [70]
						Colon cancer	In vitro	Activation of PARP-1, and caspase-9 [71]
						Breast cancer	In vitro	Upregulation of Bax and downregulation of Bcl-2 expressions [72]
13	Colchicine	Alkaloid	Colchicum automnale	C22H25NO6	399.4	Gastric cancer	In vitro, in vivo	Induce caspase-3-mediated mitochondrial apoptosis [73]
						Hypopharyngeal cancer	In vitro, in vivo	Inhibition of phosphorylated FAK/SRC complex and paxillin [74]
						Breast cancer	In vitro	Inhibition of MMP-2 expression [75]
						Colon cancer	In vitro	Decrease in AKT phosphorylation [76]
14	Combretastatin A4	Stilbene	Combretum caffrum	C18H20O5	316.3	Lung cancer	In vitro, in vivo	Disruption of microtubule assembly [77]
						Bladder cancer	In vitro, in vivo	Activation of caspase-3 and reduction in BubR1 and Bub3 expressions [78]
						Bone cancer	In vitro	Inhibition of NDRG1 [79]
15	Corosolic acid	Tripernoid	Lagerstroemia speciosa	C30H48O4	472.7	Lung cancer	In vitro, in vivo	Inhibition of VEGFR2 kinase activity [33]
						Colon cancer	In vitro, in vivo	Inhibition of HER2/HER3 receptors’ heterodimerization [80]
						Gastric cancer	In vitro	Activation of AMPK pathway [81]
						Liver cancer	In vitro, in vivo, ex vivo	Inactivation of CDK19/YAP/O-GlcNAcylation pathway [82]
						Prostate cancer	In vitro, in vivo	Activation of IRE-1/JNK, PERK/CHOP and TRIB3 [83]
						Cervical cancer	In vitro	Downregulation of PI3K and Akt signaling [84]
						Kidney cancer	In vitro	Induction of lipid ROS [85]
						Breast cancer	In vitro	Increase in ROS production and decrease in VEGF concentration [86]
						Bladder cancer	In vitro, in vivo	Upregulation of SQSTM1/P62, NBR1, and UBB expression [87]
16	Crocetin	Carotenoid	Crocus sativus	C20H24O4	328.4	Prostate cancer	In vitro, in vivo	Induce DNA damage and apoptosis [88]
						Colon cancer	In vitro	Upregulation FAS/FADD death receptor [89]
						Pancreatic cancer	In vitro, in vivo	Upregulation of Bax and downregulation of Bcl-2 protein [90]
						Gastric cancer	In vitro, in vivo	Upregulation of caspase-3, -8 and -9 [91]
17	Cucurbitacin	Triterpene	Cucumis sativus	C32H46O8	558.7	Colon cancer	In vitro	Inhibition of Hippo-YAP Signaling Pathway [92]
						Gastric cancer	In vitro, in vivo	Suppression of Akt expression [93]
						Bile duct cancer	In vitro	Downregulation of pRB, cyclin D1 and cyclin E expression [94]
						Breast cancer	In vitro	Inhibition of Stat3 and Akt signaling [95]
18	Curcumin	Curcuminoids	Curcuma longa	C21H20O6	368.38	Breast cancer	In vitro	Upregulation of PTEN/Akt signaling pathway [96]
						Gastric cancer	In vitro	Suppression of PI3K/Akt/mTOR signaling pathway [49]
						Oral cancer	In vivo	Suppression of NF-κB, and COX-2 expression [97]
						Prostate cancer	In vitro	Downregulation of NF-κB, and CXCL1 and -2 expressions [98]
						Colon cancer	In vitro	Inhibition of AMPK-induced NF-κB, uPA, and MMP9 activation [99]
						Ovarian cancer	In vitro	JAK/STAT3 pathway inhibition [100]
						Lung cancer	In vitro	Increase in FOXA2 expression [101]
19	Diosgenin	Saponin	Dioscorea villosa	C27H42O3	414.6	Breast cancer	In vitro	Downregulation of Skp2 [102]
						Liver cancer	In vitro	Inhibition of Akt and upregulation of p21 and p27 expression [103]
20	D-limonene	Terpene	Citrus aurantium	C10H16	136.23	Colon cancer	In vitro	Inactivation of Akt pathway [104]
						Lung cancer	In vitro	Upregulation of Atg5 [105]
						Prostate cancer	In vitro	Generation of ROS, and activation of caspase-3 and -9 [106]
21	Emodin	Resin	Rheum palmatum	C15H10O5	270.24	Breast cancer	In vitro	Activation of AhR-CYP1A1 signaling pathway [107]
						Lung cancer	In vitro	Suppression of HAS2-HA-CD44/RHAMM pathway [108]
						Pancreatic cancer	In vitro, in vivo	Downregulation of NF-κB, VEGF, MMP-2, and -9 [109]
						Colon cancer	In vitro	Suppression of PI3K/AKT signaling [110]
						Prostate cancer	In vitro	Downregulation of VEGF [111]
22	Epigallocatechin gallate (EGCG)	Catechin	Camellia sinensis	C22H18O11	458.4	Bile duct cancer	In vitro, in vivo	Suppression of Notch1, MMP-2, and -9 signaling [112]
						Lung cancer	In vitro	Activation of AMPK signaling pathway [113]
						Ovarian cancer	In vitro	Induce DNA damage [114]
						Prostate cancer	In vitro, in vivo	Inhibition of HSP90 function [115]
						Head & neck cancer	In vitro, in vivo	Inhibition of beta-catenin expression [116]
						Colon cancer	In vitro	Induction of ER stress through PERK/p-eIF2α/ATF4 and IRE1α pathways activation [117]
23	Erianin	Bisbenzyl	Dendrobium chrysotoxum	C18H22O5	318.4	Breast cancer	In vitro	Activation PI3K/Akt pathway [118]
						Lung cancer	In vitro, in vivo	Induction of Ca2+/CaM-dependent ferroptosis [119]
						Liver cancer	In vitro, in vivo	Induction of oxidative stress-mediated mitochondrial apoptosis [73]
						Oral cancer	In vitro	Regulation of MAPK pathway [120]
						Bladder cancer	In 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 cancer	In vitro	Activation of JNK pathway [123]
						Cervical cancer	In vitro	Regulation of ERK1/2 signaling [124]
24	Evodiamine	Alkaloid	Evodia rutaecarpa	C19H17N3O	303.4	Lung cancer	In vitro, in vivo	Elevation of CD8+ T cells and downregulation of MUC1-C/PD-L1 axis [125]
						Thyroid cancer	In vitro	Through M phase cell cycle arrest and apoptosis’s induction [126]
						Prostate cancer	In vitro	Activation of caspase-3 and -9 [127]
						Liver cancer	In vitro	Deactivation of PI3K/AKT pathway [128]
						Bladder cancer	In vitro	Enhance activation of P38 and JNK signaling [129]
						Colon cancer	In vitro, in vivo	Inhibition of acetyl-NF-κB, p65 and MMP-9 expression [130]
						Ovarian cancer	In vitro	Elevation of p27 and p21, and inhibition of Cdc2 expression [131]
						Pancreatic cancer	In vitro	Inhibition of NF-κB, p65, and Bcl-2 expression, while activate Bax and cleaved caspase-3 [132]
25	Flavopiridol	Flavonoids	Dysoxylum binectariferum	C21H20ClNO5	41.8	Breast cancer	In vitro	Inhibition of cyclin-dependent kinases [133]
						Thyroid cancer	In vitro, in vivo	Reduction in Cyclin-dependent kinases (CDK) and MCL1 levels [134]
						Bile duct cancer	In vitro, in vivo	Suppression of cyclin-dependent kinase pathway [135]
						Head & neck cancer	In vitro, in vivo	Reduction in cyclin D1 expression [136]
						Lung cancer	In vitro	Reduction in E-cadherin level [137]
						Esophageal cancer	In vitro, in vivo	Decrease in c-Myc expression [138]
26	Gallic Acid	Phenolic acid	Galanthus nivalis	C7H6O5	170.12	Lung cancer	In vitro, in vivo	Inhibition of PI3K/Akt pathway [139]
						Liver cancer	In vitro	Suppression of Wnt/β-catenin signaling [140]
						Breast cancer	In vitro, in vivo	Increases expression of cleaved caspase-7, -9, and p53, while reduces expression of Bcl-2, and PARP [141]
						Colon cancer	In vitro, in vivo	Inhibition of SRC and EGFR phosphorylation [142]
						Gastric cancer	In vitro	Increases expression of caspase-3, -8, and P53 gene [143]
						Prostate cancer	In vitro	Generation of ROS [144]
						Ovarian cancer	In vitro, in vivo	Inhibition of carbonic anhydrase IX protein [145]
						Pancreatic cancer	In vitro	Downregulation of protein Bcl-,2 while increases in BAX expression [146]
27	Gambogic acid	Resin	Garcinia hanburyi	C38H44O8	628.7	Lung cancer	In vitro, in vivo	Downregulation of Bcl-2, and upregulation of Bax expression [147]
						Breast cancer	In vitro, in vivo	Increase the expression of Fas, cleaved caspase-3, -8, -9 and Bax proteins [148]
						Liver cancer	In vitro	Induces apoptosis through caspases 3, -7, -8 and -9 [149]
						Prostate cancer	In vitro	Induction of ROS production [150]
						Colon cancer	In vitro, in vivo	Inhibition of Akt-mTOR signaling [151]
						Gastric cancer	In vitro, in vivo	Downregulation of circ_ASAP2 and CDK7, while upregulation of miR-33a-5p expression [152]
28	Genistein	Isoflavones	Glycine max	C15H10O5	270.24	Liver cancer	In vitro	Upregulation of Bax, cleaved caspase-3 and -9 and downregulation of Bcl-2 expression [153]
						Colon cancer	In vitro, in vivo	Suppression of MiR-95, Akt and SGK1 signaling [154]
						Prostate cancer	In vitro, in vivo	Decrease MMP-2 expression [155]
						Lung cancer	In vitro	Downregulation of FoxM1 [156]
29	Gingerol	Phenol	Zingiber officinale	C17H26O4	294.4	Breast cancer	In vitro	Induction of p53-dependent intrinsic apoptosis [157]
						Oral cancer	In vitro	Activate caspases and increase Apaf-1 expression [158]
						Cervical cancer
						Lung cancer	In vitro, in vivo	Reduction in ROS and iron accumulation and suppression of USP14 expression [159]
						Pancreatic cancer	In vitro	Inhibition of PI3K/AKT signaling [160]
30	Ginkgetin	Flavonoid	Ginkgo biloba	C32H22O10	566.5	Breast cancer	In vitro	Downregulation of estrogen receptor [161]
						Lung cancer	In vitro, in vivo	Inhibition of p62/SQSTM1 signaling [162]
						Prostate cancer	In vitro, in vivo	Suppression of STAT3 expression [163]
						Bone cancer	In vitro	Inhibition of STAT3 and activation of caspase-3/9 [164]
						Ovarian cancer	In vitro	Induction of apoptosis by activation of caspase-3 [165]
						Kidney cancer	In vitro	Suppression of JAK2-STAT3 pathway [166]
31	Glycyrrhizin	Triterpenes	Glycyrrhiza glabra	C42H62O16	822.9	Breast cancer	In vitro, in vivo	Induces ROS-mediated apoptosis [167]
						Gastric cancer	In vitro	Downregulation of PI3K/AKT pathway [168]
						Prostate cancer	In vitro	Induces DNA damage [169]
						Ovarian cancer	In vitro	Upregulation of Fas and FasL expression [170]
32	Gossypol	Phenol	Gossypium hirsutum	C30H30O8	518.6	Colon cancer	In vitro	Suppression of genes coding expression for CLAUDIN1, FAS, IL2, and IL8 [171]
						Breast cancer	In vitro	Suppression of IKBKE, CCL2 and MAPK1 expression [172]
						Lung cancer	In vitro	Decrease EGFR phosphorylation and AKT/ERK signaling [173]
						Prostate cancer	In vitro	Activation of p53 protein [174]
						Ovarian cancer	In vitro	Cause changes in thiol/redox states of proteins associated with glycolysis and stress responses [175]
						Cervical cancer	In vitro, in vivo	Inhibition of FAK signaling and reversing TGF-β1-induced EMT [176]
						Head & neck cancer	In vivo	Inhibition of Bcl-XL expression [177]
						Skin cancer	In vitro	Induces mitochondria-dependent apoptosis [178]
33	Harmine	Alkaloid	Peganum harmala	C13H12N2O	212.25	Breast cancer	In vitro, in vivo	Downregulation of TAZ [179]
						Thyroid cancer	In vitro, in vivo	Downregulation of Bcl-2 and upregulation of Bax expression [180]
						Gastric cancer	In vitro	Inhibition of Akt/mTOR/p70S6K signaling [181]
						Pancreatic cancer	In vitro	Suppression of AKT/mTOR pathway [182]
						Ovarian cancer	In vitro	Inhibition of ERK/CREB pathway [183]
						Lung cancer	In vitro	Suppression of AKT phosphorylation and enhances ROS generation [184]
34	Hesperidin	Flavonoid	Citrus limon	C28H34O15	610.6	Lung cancer	In vitro	Downregulation of FGF and NF-κB signal transduction pathways [185]
						Gastric cancer	In vitro	Increase in ROS levels and regulation of MAPK signaling [135]
						Liver cancer	In vitro	Downregulation of Bcl-xL and upregulation of Bax, Bak, and tBid proteins [186]
						Skin cancer	In vitro	Induces DNA damage [187]
						Prostate cancer	In vitro	Induces apoptosis triggered by ROS generation [188]
						Breast cancer	In vitro	Inhibition of PD-L1 expression via downregulation of Akt and NF-κB signaling [189]
35	Hispidulin	Flavone	Salvia involucrate	C16H12O6	300.26	Lung cancer	In vitro, in vivo	Induces ROS-mediated apoptosis via ER stress pathway [190]
						Liver cancer	In vitro, in vivo	Upregulation of PPARγ signaling [191]
						Kidney cancer	In vitro, in vivo	Activation of ROS/JNK signaling [192]
						Gastric cancer	In vitro	Activate ERK1/2 and NAG-1 signaling [193]
36	Kaempferol	Flavonoid	Spinacia oleracea	C15H10O6	286.24	Breast cancer	In vitro	Increase expression of H2AX, caspase-3, and -9 [194]
						Liver cancer	In vitro	Activation of AMPK signaling [195]
						Kidney cancer	In vitro	Downregulation of AKT and FAK pathways [196]
						Cervical cancer	In vitro	Disruption of mitochondrial membrane potential and intracellular free Ca2+ concentration [197]
						Pancreatic cancer	In vitro	Inhibition of TGM2 expression [198]
						Colon cancer	In vitro	Activation of ATM and p53-Bax axis [199]
37	Kurarinone	Flavonoid	Sophora flavescens	C26H30O6	438.5	Lung cancer	In vitro, in vivo	Suppression of caspase-7 and -12, and AKT pathway [200]
						Gastric cancer	In vitro	Inhibition of STAT3 signaling [201]
						Breast cancer	In vitro	Inhibition of NF-κB activation [202]
38	Lappaconitine	Diterpenoid	Aconitum sinomontanum	C32H44N2O8	584.7	Colon cancer	In vitro	Downregulation of PI3K/AKT/GSK3β signaling [203]
						Lung cancer	In vitro	Downregulation of Cyclin E1 expression [204]
						Liver cancer	In vitro	Upregulation of Bax, P53, and downregulation of Bcl-2 expressions [205]
39	Licochalcone A	Chalcone	Glycyrrhiza glabra	C21H22O4	338.4	Breast cancer	In vitro	Inhibition of PI3K/Akt/mTOR pathway [206]
						Bladder cancer	In vitro	Induces ER stress-dependent apoptosis caused by activation of ER-specific caspase-12 [207]
						Lung cancer	In vitro	Induces ERK and p38 activation while suppresses JNK signaling [208]
						Liver cancer	In vitro	Downregulation of MKK4/JNK [209]
40	Liriodenine	Alkaloid	Enicosanthellum pulchrum	C17H9NO3	275.26	Breast cancer	In vitro	Upregulation of p53 [210]
						Lung cancer	In vitro	Lockage of cell cycle progression at the G2/M phase [211]
						Ovarian cancer	In vitro	Inhibition of progression of CAOV-3 cell cycle in S phase [212]
41	Luteolin	Flavonoid	Reseda luteola	C15H10O6	286.24	Liver cancer	In vitro	Increases caspase-8 and decreases Bcl-2 expression [213]
						Colon cancer	In vitro	Upregulation of Nrf2 expression [214]
						Gastric cancer	In vitro	Inhibition of STAT3 phosphorylation [215]
						Oral cancer	In vitro	Suppression of EMT-induced transcription factors [216]
						Breast cancer	In vitro	Suppression of NF-κB/c-Myc activation and hTERT transcription [217]
						Pancreatic cancer	In vitro	Inhibition of VEGF expression [218]
						Lung cancer	In vitro	Inhibition of FAK-Src signaling [219]
42	Lycopene	Carotenoid	Solanum lycopersicum	C40H56	536.9	Breast cancer	In vitro	Inhibition of Akt phosphorylation [220]
						Prostate cancer	In vitro, in vivo	Downregulation of IL1, IL6, IL8, and TNF-α levels [221]
						Colon cancer	In vitro	Suppression of NF-κB and JNK signaling [222]
						Pancreatic cancer	In vitro	Inhibition of ROS-Mediated NF-κB Signaling [223]
						Lung cancer	In vitro, in vivo	Induction of RARβ expression [224]
						Gastric cancer	In vivo	Increase in SOD, and CAT, while decrease in MDA levels [225]
						Cervical cancer	In vitro	Upregulation of Bax, and downregulation of Bcl-2 expression [226]
						Skin cancer	In vivo	Inhibition of PCNA expression [227]
						Brain cancer	In vitro	Activation of caspase-3 pathway [228]
						Ovarian cancer	In vitro, in vivo	Decrease in integrin α5 expression and MAPK activation [229]
43	Lycorine	Alkaloid	Crinum asiaticum	C16H17NO4	287.31	Breast cancer	In vitro, in vivo	Inhibition of STAT3 signaling pathway [230]
						Gastric cancer	In vitro, in vivo	Enhances FBXW7-MCL1 axis level [224]
						Prostate cancer	In vitro, in vivo	Inhibition of JAK/STAT signaling [231]
						Lung cancer	In vitro, in vivo	Inhibition of Wnt/β-catenin signaling [232]
						Liver cancer	In vitro	inhibition of ROCK1/cofilin-induced actin dynamics [233]
44	Magnolol	Lignan	Magnolia officinalis	C18H18O2	266.3	Lung cancer	In vitro, in vivo	Downregulation of Akt/mTOR pathway [234]
						Gallbladder cancer	In vitro, in vivo	Increase in p53 expression [235]
						Liver cancer	In vitro	Inhibition of ERK-modulated metastatic process [236]
						Prostate cancer	In vitro	Downregulation of MMP-2 and MMP-9 expression [237]
						Esophageal cancer	In vitro	Activation of MAPK pathway [238]
45	Matrine	Alkaloid	Sophora flavescens	C15H24N2O	248.36	Prostate cancer	In vitro	Enhances expression of GADD45B, tumor suppresser gene or AKT/GSK3β/β-catenin [239]
						Ovarian cancer	In vitro, in vivo	Suppression of PI3K/AKT/mTOR pathway expression [240]
						Colon cancer	In vitro	Upregulation of Bax, downregulation of Bcl-2, and activation of caspase-3 and -9 [241]
						Liver cancer	In vitro, in vivo	Upregulation of miR-345-5p and downregulation of circ_0027345 and HOXD3 [242]
						Lung cancer	In vitro	Downregulation of C-C chemokine receptor type 7 (CCR7) [243]
46	Myricetin	Flavonoid	Myrica nagi Thunb	C15H10O8	318.23	Thyroid cancer	In vitro	DNA damaging and inducing the release of apoptosis-inducing factor (AIF) [244]
						Bladder cancer	In vitro, in vivo	Activation of caspase-3, and inhibition of Akt and MMP-9 expression [245]
						Colon cancer	In vitro	Increases BAX/BCL2 ratio and AIF release [246]
						Prostate cancer	In vitro	Inhibition of PIM1 and disruption of PIM1/CXCR4 interaction [247]
						Breast cancer	In vitro	Enhances intracellular ROS production [248]
						Lung cancer	In vitro	Inhibition of FAK-ERK signaling pathway [249]
47	Nimbolide	Limonoid triterpene	Azadirachta indica	C27H30O7	466.5	Pancreatic cancer	In vitro, in vivo	Reduction in PI3K/AKT/mTOR and ERK signaling [250]
						Colon cancer	In vitro, in vivo	Inhibition of Bcl-x, CXCR4, VEGF, and NF-κB [251]
						Bladder cancer	In vitro	Stimulation of p38 MAPK and AKT phosphorylation [252]
48	Noscapine	Alkaloid	Papaver somniferum	C22H23NO7	413.4	Colon cancer	In vitro	Inhibition of PI3K/AKT/mTOR pathway [253]
						Breast cancer	In vitro	Decreases NF-κB and increases IκBα expression [254]
						Lung cancer	In vitro, in vivo	Upregulation of PARP, Bax, and repression of Bcl2 expression [255]
						Prostate cancer	In vivo	Suppression of microtubule dynamics [256]
49	Oridonin	Diterpenoid	Rabdosia rubescens	C20H28O6	364.4	Colon cancer	In vitro, in vivo	Downregulation of GLUT1 and induction of autophagy [257]
						Liver cancer	In vitro, in vivo	Inhibition of Akt pathway [258]
						Ovarian cancer	In vitro	Suppression of mTOR pathway [259]
						Bladder cancer	In vitro, in vivo	Inactivation of ERK and AKT signaling pathways [260]
						Esophageal cancer	In vitro, in vivo	Suppression of AKT signaling [261]
						Breast cancer	In vitro	Decrease in expression of MMPs and regulation of Integrin β1/FAK pathway [262]
						Bone cancer	In vitro, in vivo	Activation of PPAR-γ and inhibition of Nrf2 pathways [263]
50	Oxymatrine	Alkaloid	Sophora flavescens	C15H24N2O2	264.36	Cervical cancer	In vitro	Suppression of AKT/mTOR [264]
						Breast cancer	In vitro	Suppress the PI3K/Akt [265]
						Pancreatic cancer	Ion vitro	Downregulation of Livin and Survivin expression and upregulation of Bax/Bcl-2 ratio [266]
						Prostate cancer	In vitro, in vivo	Increase in expression of p53 and Bax, and decrease in Bcl-2 level [267]
51	Physapubescin B	Steroid	Physalis pubescens	C30H42O8	530.6	Ovarian cancer	In vitro	Suppress transcriptional activity of STAT3 [268]
						Kidney cancer	In vitro, in vivo	Decreases expression of HIF-2α and activation of caspase-3 and -8 [269]
52	Pinostrobin	Flavonoid	Boesenbergia rotunda	C16H14O4	270.28	Cervical cancer	In vitro	Increases expressions of TRAIL, FADD and production of ROS [270]
						Breast cancer	In vitro	Downregulation of FAK and RhoA signaling [271]
						Lung cancer	In vitro	Via promoting apoptosis [272]
						Prostate cancer	In vitro	Decrease in cyclins B expression [273]
53	Piperine	Alkaloid	Piper nigrum	C17H19NO3	285.34	Colon cancer	In vitro	Suppression of Wnt/β-catenin pathway [274]
						Lung cancer	In vitro	Induces p53-mediated cell cycle arrest and apoptosis via activation of caspase-3 and -9 cascades [275]
						Breast cancer	In vitro, in vivo	Induction of cell apoptosis and cell cycle blockage [276]
						Prostate cancer	In vitro	Downregulation of cyclin A & D1 [277]
54	Piperlongumine	Alkaloid	Piper longum	C17H19NO5	317.34	Lung cancer	In vitro	Inhibition of Akt phosphorylation [278]
						Prostate cancer	In vitro	Induces DNA damage [279]
						Colon cancer	In vitro	Induces DNA damage via increasing ROS production [280]
55	Plumbagin	Alkaloid	Plumbago zeylinica	C11H8O3	188.18	Breast cancer	In vitro	Upregulation of p53 and p21 [281]
						Colon cancer	In vitro	Induction of ROS formation [282]
						Liver cancer	In vitro, in vivo	Downregulation of SIVA/mTOR signaling [283]
						Prostate cancer	In vitro, in vivo	Induction of ROS production, and activation of ER stress [284]
						Lung cancer	In vitro	Activation of caspase-9 and ROS production [285]
						Esophageal cancer	In vitro, in vivo	Inhibition of STAT3-PLK1-AKT signaling [286]
						Bone cancer	In vitro	Downregulation of c-Myc expression [287]
						Cervical cancer	In vitro	Downregulation of MMP 2, 9, β-catenin and N-cadherin, while upregulation of E-cadherin signaling [288]
56	Pristimerin	Triterpenoid	Mortonia greggii	C30H40O4	464.6	Colon cancer	In vitro	Decreases in AKT expression [289]
						Oral cancer	In vitro	Inhibition of MAPK/Erk1/2 and Akt signaling [290]
						Prostate cancer	In vitro	Inhibition of HIF-1α [291]
						Lung cancer	In vitro	Downregulation of integrin β1 and MMP2 expression [292]
						Pancreatic cancer	In vitro	Inhibition of Akt/NF-κB/mTOR signaling [293]
57	Pterostilbene	Stilbenoid	Polygonum cuspidatum	C16H16O3	256.3	Ovarian cancer	In vitro	Decreases release of NF-κB p50, and NF-κB p65 [294]
						Lung cancer	In vitro, in vivo	Enhance ROS generation, caspase-3 activity and ER stress [295]
						Breast cancer	In vitro	Inactivate AKT and mTOR signaling pathways [296]
						Colon cancer	In vitro, in vivo	Facilitate DNA repairing mediated through Top1/Tdp1 pathway [297]
58	Puerarin	Isoflavone	Pueraria radix	C21H20O9	416.4	Colon cancer	In vitro	Increase Bax expression and caspase-3 activation [298]
						Prostate cancer	In vitro	Inhibition of Keap1/Nrf2/ARE signaling pathways [299]
						Lung cancer	In vitro, in vivo	Inhibition of PI3K/Akt pathway [300]
						Liver cancer	In vitro	Modulation of MAPK signaling pathway [301]
						Brain cancer	In vitro	Suppression of p-Akt and Bcl-2, while enhancement of Bax and cleaved caspase-3 expression [302]
59	Quercetin	Flavonoid	Allium cepa	C15H10O7	302.23	Thyroid cancer	In vitro	Upregulation of Pro-NAG-1/GDF15 [303]
						Breast cancer	In vitro	Inactivation of caspase-3 pathway [304]
						Liver cancer	In vitro	Inhibition of PI3K/Akt and ERK pathways [305]
						Prostate cancer	In vitro	Enhances release of tumor suppressor genes i.e., PTEN, p53 and TSC [306]
						Lung cancer	In vitro	Inhibition of NF-κB Signaling [307]
60	Resveratrol	Stilbenoid	Polygonum cuspidatum	C14H12O3	228.24	Colon cancer	In vitro	Inactivates PI3K/Akt signaling [308]
						Breast cancer	In vitro	Suppression of Integrin αvβ3 expression [309]
						Ovarian cancer	In vitro	Inactivation of STAT3 signaling [310]
						Pancreatic cancer	In vitro	Suppression of NAF-1 expression, induces ROS accumulation, and activation of Nrf2 signaling [311]
						Gastric cancer	In vitro	Upregulation of Bax, cleaved caspase-3 and -8 while suppression of NF-κB activation [312]
						Lung cancer	In vitro, in vivo	Decreases SIRT1-mediated NF-κB activation [313]
						Skin cancer	In vitro, in vivo	Deacetylation of SIRT1-activated NF-κB [314]
61	Rutin	Flavonoid	Ruta graveolens	C27H30O16	610.5	Colon cancer	In vitro	Inhibition of caspase-3 expression [315]
						Brain cancer	In vitro	Upregulation of P53 expression [265]
						Skin cancer	In vitro	Suppression of PI3K/Akt and Wnt/β-catenin signaling [316]
						Breast cancer	In vitro, in vivo	Inhibition of tyrosine kinase c-Met receptor [317]
62	Safranal	Alkaloid	Crocus sativus	C10H14O	150.22	Colon cancer	In vitro	Suppression of PI3K/Akt/ mTOR pathway [318]
						Liver cancer	In vitro	Activation of caspases-8 and -9 [319]
						Prostate cancer	In vitro, in vivo	Downregulation of AKT and NF-κB signaling [320]
						Breast cancer	In vitro	Inhibits DNA and RNA synthesis [321]
63	Shikonin	Quinone	Lithospermum erythrorhizon	C16H16O5	288.29	Lung cancer	In vitro	Downregulation of PFKFB2 expression [322]
						Colon cancer	In vitro	Reduction in peroxiredoxin V (PrxV) expression [323]
						Prostate cancer	In vitro	Induces necroptosis by decreasing caspase-8 and increasing pRIP1 and pRIP3 [324]
						Liver cancer	In 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 cancer	In vitro, in vivo	Inhibition of MAPK pathway-mediated induction of apoptosis [327]
						Bile duct cancer	In vitro	Inhibitions of PKM2 expression [328]
						Breast cancer	In vitro	Inhibition of epidermal growth factor receptor signaling [329]
64	Shogaol	Phenol	Zingiber officinale	C17H24O3	276.4	Breast cancer	In vitro	Inhibition Akt and STAT signaling pathway [330]
						Prostate cancer	In vitro, in vivo	Inhibition of STAT3 and NF-κB signaling [331]
						Lung cancer	In vitro, in vivo	Inhibits secretion of CCL2 [332]
						Cervical cancer	In vitro	Induces apoptosis and G2/M cell cycle arrest [333]
65	Silibinin	Flavonolignan	Silybum marianum	C25H22O10	482.4	Breast cancer	In vivo	Inhibition of EGF–EGFR signaling pathway [334]
						Lung cancer	In vitro, in vivo	Activation of EGFR/LOX pathway [335]
						Ovarian cancer	In vitro, in vivo	Inhibition of ERK and Akt pathway [336]
						Prostate cancer	In vitro	Suppression of vimentin and MMP-2 expression [337]
						Skin cancer	In vivo	Via Pro-Oxidant activity [338]
						Colon cancer	In vitro	Downregulation of COX-2, VEGF, MMP-2, & -9, and CXCR-4 expression [339]
						Gastric cancer	In vitro	Inhibition of STAT3 pathway [340]
66	Silymarin	Flavonolignan	Silybum marianum	C25H22O10	482.4	Oral cancer	In vitro, in vivo	Induction of DR5/caspase-8 apoptotic signaling [289]
						Gastric cancer	In vitro	Inhibition of p-ERK and activation of p-p38 and p-JNK pathways [341]
						Colon cancer	In vitro	Increases ATF3 transcription through activation of JNK and IκK-α [291]
						Prostate cancer	In vitro	Inhibition of cyclins (A, B1, D, E) and cyclin-dependent kinase pathway [337]
						Breast cancer	In vitro, in vivo	Regulation of MAPK signaling pathway [342]
						Liver cancer	In vivo	Reduction in ROS levels [343]
67	Solamargine	Alkaloid	Solanum nigrum L.	C45H73NO15	868.1	Gastric cancer	In vitro, in vivo	Inhibition of Erk1/2 MAPK phosphorylation [344]
						Skin cancer	In vitro	Downregulation of hILP/XIAP [345]
						Bone cancer	In vitro	Suppression of notch pathway [346]
						Liver cancer	In vitro	Induction of apoptosis [347]
						Prostate cancer	In vitro, in vivo	Suppression of MUC1 expression [348]
68	Stachydrine	Alkaloid	Herba Leonuri	C7H13NO2	143.18	Breast cancer	In vitro	Inhibition of Akt/ERK pathways [349]
						Prostate cancer	In vitro	Inhibits CXCR3 and CXCR4 expressions [350]
69	Sugiol	Diterpene	Salvia prionitis	C20H28O2	300.4	Ovarian cancer	In vitro	Blockage of RAF/MEK/ERK signaling pathway [351]
						Prostate cancer	In vitro, in vivo	Inhibits STAT3 activity and increase ROS level [352]
						Pancreatic cancer	In vitro	Induces ROS-mediated alterations in MMP [353]
						Uterine cancer	In vitro	Increases Bax and decreases Bcl-2 expressions [354]
70	Tanshinone	Terpenoids	Salvia miltiorrhiza	C18H12O3	276.3	Lung cancer	In vitro, in vivo	Suppression of IL-8 through NF-κB and AP-1 Pathways [355]
						Gastric cancer	In vitro, in vivo	Downregulation of STAT3 pathway [356]
						Breast cancer	In vitro	Suppression of HIF-1α and VEGF [357]
						Ovarian cancer	In vitro, in vivo	Downregulation of Bcl-2, VEGF, COX2 and upregulation of Bax expressions [358]
						Bladder cancer	In vitro	Activation of caspases 3 and -9 [359]
						Cervical cancer	In vitro	Decrease in Bcl-2, HPV 16 and E7 protein levels, while increase in Bax and caspase-3 expressions [360]
71	Tectochrysin	Flavonoids	Alpinia oxyphylla	C16H12O4	268.26	Colon cancer	In vitro	Inhibition of NF-κB signaling [361]
						Prostate cancer	In vitro	Suppression of PI3K/AKT pathway [362]
						Lung cancer	In vitro	Inhibition of STAT3 signaling [363]
72	Tetrandrine	Alkaloid	Stephania tetrandra	C38H42N2O6	622.7	Cervical cancer	In vitro, in vivo	Downregulation 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 cancer	In vitro, in vivo	Activation of caspase-3 and -9, and upregulation of apaf-1 [366]
						Colon cancer	In vitro	Inhibition of EMT transition [367]
						Prostate cancer	In vitro	Induction of DR4 and DR5 expression, and TRAIL-mediated apoptosis [368]
						Bone cancer	In vitro, in vivo	Inhibition of PTEN/Akt, MAPK/Erk and Wnt signaling pathways [369]
73	Thymol	Phenol	Thymus vulgaris	C10H14O	150.22	Lung cancer	In vitro	Enhances cytoplasmic membrane permeability and cell apoptosis [370]
						Breast cancer
						Prostate cancer
						Colon cancer	In vitro	Suppression of Wnt/β-Catenin pathway [371]
						Gastric cancer	In vitro	Activation of Bax, PARP, and caspase-8 proteins [372]
74	Thymoquinone	Quinone	Nigella sativa	C10H12O2	164.2	Kidney cancer	In vitro	Inhibition of AKT phosphorylation [373]
						Breast cancer	In vitro, in vivo	Through phosphorylation of p38 via ROS generation [374]
						Bladder cancer	In vitro	Inhibition of mTOR signaling [375]
						Colon cancer	In vitro	Inhibition of STAT3, JAK2- and EGF receptor tyrosine kinase [376]
						Gastric cancer	In vitro, in vivo	Inhibition of STAT3 pathway [377]
						Liver cancer	In vitro	Inhibition of IL-8 expression, and activation of TRAIL receptors [378]
						Lung cancer	In vitro	Reduction in ERK1/2 phosphorylation [379]
						Oral cancer	In vitro	Downregulation of p38β MAPK [380]
						Pancreatic cancer	In vitro	Downregulation of mucin 4 expression [381]
75	Ursolic acid	Triterpenoids	Oldenlandia diffusa	C30H48O3	456.7	Ovarian cancer	In vitro	Downregulation of PI3K/AKT pathway [382]
						Lung cancer	In vitro	Enhances apoptosis-inducing factor (AIF) and endonuclease G release [383]
						Colon cancer	In vitro, in vivo	Inhibition of IL-6-mediated STAT3 pathway [384]
						Breast cancer	In vitro	Downregulation of Nrf2 expression [385]
						Pancreatic cancer	In vitro, in vivo	Inhibition of NF-κB and STAT3 pathways [386]
						Gallbladder cancer	In vitro	Activation of caspase-3, -9 and PARP pathway [387]
76	Withaferin-A	steroidal lactone	Withania somnifera	C28H38O6	470.6	Breast cancer	In vitro	Inhibition of TASK-3 expression [388]
						Oral cancer	In vitro	Upregulation of Bim and Bax expression [389]
						Skin cancer	In vitro	Activation of TRIM16 [390]
						Bone cancer	In vitro	Inactivation of Notch-1 signaling [391]
						Colon cancer	In vitro, in vivo	Inhibition of STAT3 Transcriptional activity [392]
77	Wogonin	Flavonoid	Scutellaria baicalensis	C16H12O5	284.26	Colon cancer	In vitro	Increases ER stress, and mediates p53 phosphorylation [393]
						Cervical cancer	In vitro	Inhibition of Cdk4 and cyclin D1 [394]
						Lung cancer	In vitro	Downregulation of SGK1 protein levels [395]
						Bone cancer	In vitro	Increases ROS level [396]
						Breast cancer	In vitro	Activation of ERK and p38 MAPKs pathways [397]
						Ovarian cancer	In vitro	Increase in p53 and decrease in VEGF proteins expression [398]
78	Xanthatin	Sesquiterpene lactone	Xanthium strumarium	C15H18O3	246.3	Skin cancer	In vitro, in vivo	Inhibition of Wnt/β-catenin pathway [399]
						Lung cancer	In vitro, in vivo	Inhibition of GSK-3β signaling [400]
						Breast cancer	In vitro, in vivo	Inhibition of VEGFR2 signaling [401]
						Colon cancer	In vitro	Inhibition of mTOR pathway [402]

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).

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.

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).

Table 3

Number of effective phytochemicals against different types of cancer.

Cancer Type	Number of Phytochemicals	Cancer Type	Number of Phytochemicals	Cancer Type	Number of Phytochemicals
Breast cancer	55	Pancreatic cancer	18	Esophageal cancer	6
Colon cancer	53	Cervical cancer	14	Thyroid Cancer	6
Lung cancer	53	Bladder cancer	13	Bile duct cancer	5
Prostate cancer	45	Bladder cancer	13	Brain cancer	5
Liver cancer	30	Skin cancer	11	Miscellaneous	10
Ovarian Cancer	27	Oral cancer	9	NA	NA
Gastric cancer	24	Kidney cancer	7	NA	NA

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).

Table 4

Phytochemicals with activity against different number of cancer types.

Sr #	Phytochemicals	Effective against Number of Cancer Types
1	Lycopene	10
2	Baicalin, Corosolic acid, Plumbagin, Shikonin, Thymoquinone	9
3	Erianin, Evodiamine, Gallic acid, Gossypol	8
4	Apigenin, Curcumin, Luteolin, Oridonin, Resveratrol, Silibinin	7
5	Other phytochemicals	≤6

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).

Table 5

List of phytochemicals approved by the FDA or in clinical trials for various types of cancer.

Sr #	Phytochemicals	Source	Cancer Type	Development Stage	Status	Trade Name	NCT Number
1	Vincristine	Catharanthus roseus	Acute leukemia	FDA approved	1963	Oncovin	NA
2	Paclitaxel	Taxus braciola	Late-stage pancreatic cancer	FDA approved	2013	Abraxane®	NA
			Advanced non-small cell lung cancer	FDA approved	2012	Abraxane®	NA
			Metastatic breast cancer	FDA approved	2005	Abraxane®	NA
3	Curcumin	Curcuma longa	Prostate cancer	Phase 3	Recruiting, 15 June 2021	Biocurcumax (BCM-95) ®	NCT03769766
			Cervical cancer	Phase 2	Not yet recruiting, 25 June 2021	Curcugreen (BCM-95) ®	NCT04294836
			Pancreatic cancer	Phase 2	Recruiting, 2020	NA	NCT00094445
			Gastric cancer	Phase 2	Not yet recruiting, 13 January 2022	Meriva®	NCT02782949
			Breast cancer	Phase 1	Recruiting, 23 February 2021	NA	NCT03980509
4	Lycopene	Solanum lycopersicum	Prostate cancer	Phase 3	Completed, 23 January 2018	NA	NCT01105338
5	Resveratrol	Polygonum cuspidatum	Multiple myeloma cancer	Phase 2	Terminated (collecting more data) 27 February 2019	SRT501	NCT00920556
			Colon cancer	Phase 1	Completed, 14 June 2017	SRT501	NCT00920803
			Neuroendocrine cancer	NA	Completed, 18 November 2019	NA	NCT01476592
6	Capsaicin	Capsicum annuum	Breast cancer	Phase 3	Recruiting, 29 December 2021	Qutenza®	NCT03794388
			Head and neck cancer	Phase 2	Recruiting, 5 August 2021	Qutenza®	NCT04704453
			Prostate cancer	Phase 2	Not yet recruiting, 16 January 2014	Cayenne	NCT02037464
7	Chlorogenic acid	Etlingera elatior	Lung cancer	Phase 2	Recruiting, 26 November 2018	NA	NCT03751592
8	Colchicine	Colchicum autumnale	Liver cancer	Phase 2	Recruiting, 11 February 2020	Colchicine	NCT04264260
9	Genistein	Glycine max	Prostate cancer	Phase 2	Temporarily suspended, 4 December 2020	NA	NCT02766478
			Colorectal cancer	Phase 2	Completed, 10 May 2019	Bonistein	NCT01985763
			Prostate cancer	Phase 2	Completed, 6 August 2019	Novasoy 400	NCT01036321
			Bladder cancer	Phase 2	Completed, 10 June 2021	NA	NCT00118040
10	Camptothecin	Camptotheca acuminata	Solid tumor	Phase 2	Completed, 28 May 2020	CRLX101	NCT00333502
			Stomach and esophageal cancer	Phase 2	Completed, 1 February 2018	CRLX101	NCT01612546
			Advanced non-small cell lung cancer	Phase 2	Completed, 28 May 2020	CRLX101	NCT01380769
11	Piperine	Piper nigrum	Prostate cancer	Phase 2	Not yet recruiting, 3 November 2021	NA	NCT04731844
12	Silibinin	Silybum marianum	Prostate cancer	Phase 2	Completed, 31 March 2014	Silibin-Phytosome	NCT00487721
13	Quercetin	Allium cepa	Squamous cell carcinoma	Phase 2	Recruiting, 28 October 2021	NA	NCT03476330
14	Epigallocatechin gallate	Camellia sinensis	Colon cancer	Phase 1	Recruiting, 15 December 2021	Teavigo™	NCT02891538
			Esophageal cancer	Phase 1	Recruiting, 10 September 2021	NA	NCT05039983

Figure 4

Structures of anticancer phytochemicals approved by FDA or in clinical trials.

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.