Screening the Active Phytochemicals From Eclipta prostrata and Unraveling Their Molecular Insight Into Human Malignancies.

Abbreviations

apoptosis‐inducing factor

cyclin‐dependent kinases

interleukin‐1 beta

mitogen‐activated protein kinase

microRNA

mammalian target of rapamycin

nuclear factor‐kappa B

programmed death‐ligand 1

phosphoinositide 3‐kinase

tumor necrosis factor‐alpha

wingless/integrated

Introduction

Cancer has emerged as a major worldwide health concern, and both prevalence and mortality are frequently increasing [ 1 ]. According to Cancer Statistics 2024, in the United States of America, official new cases and deaths were estimated at 2,001,140 and 611,720, respectively, by around 60 different types of cancers [ 2 ]. Usually, a mix of environmental variables and genetic abnormalities leads to the development of cancer. Tobacco use, radiation exposure, exposure to hazardous chemicals, certain diseases, and inherited genetic mutations are common causes [ 3 ]. Surgery, chemotherapy, radiation therapy, and immunotherapy are some of the modern cancer therapies that have greatly increased patient survival rates and quality of life [ 4 ]. However, these treatments come with considerable side effects due to their impact on healthy cells, and many cancers develop resistance to these therapies over time, rendering them less effective [ 5 ]. There is also a pressing need for treatments that are more specific to cancer cells, minimizing damage to normal tissues and reducing adverse effects [ 6 ]. Therefore, the importance of developing new drugs for cancer cannot be overstated. Understanding the biology of cancer has led to new opportunities for tailored medicines that target cancer cells according to their distinct genetic and genomic profiles [ 7 ]. These novel treatments promise to be more effective and less toxic than traditional therapies [ 8 , 9 ]. The ongoing research and development of new cancer drugs are crucial for overcoming the limitations of current treatments and improving outcomes for cancer patients worldwide.

The chemopreventive properties of numerous natural compounds have been investigated recently [ 10 ]. Because they are more readily available, have fewer side effects, and are more affordable than modern hormone treatments or chemotherapy, numerous extracts from natural sources have been demonstrated to have beneficial effects against cancer [ 11 ]. As a result, they make up around 60% of all anticancer medications and have drawn interest from researchers as possible anticancer treatments [ 12 ]. The evaluation of conventional phytomedicines for cytotoxic action could aid in the advancement of new chemotherapy regimens, either in separation or in conjunction with already available chemotherapy medications, to treat different forms of cancer [ 13 ].

Eclipta prostrata, also known as “False Daisy” or “Bhringraj,” belongs to the family of Asteraceae and is indigenous to a number of regions, including India, Brazil, China, and Thailand [ 14 , 15 , 16 ]. According to previous research, E. prostrata contains a range of phytochemicals, including flavonoids, alkaloids, terpenoids, and coumarins, known for their many biological actions, including antioxidant, anti‐inflammatory, and anticancer qualities [ 17 ]. Traditional medicine has traditionally employed this plant's leaves, stems, and roots to address a variety of medical conditions, together with liver illnesses, skin illnesses, and respiratory conditions [ 18 , 19 ]. Regarding cancer, research on this plant extract from different solvents has been conducted against numerous cancers [ 20 , 21 , 22 ]. However, the therapeutic effect of specific phytochemicals from this plant against cancer has not yet been explored, such as identifying phytochemicals and their impact on different human malignancies. Therefore, in this review, we aimed to screen all phytochemicals available at E. prostrata and explore the chemotherapeutic activities of each phytochemical. After finding active phytochemicals, we planned to unravel their synergistic activity with conventional drugs, nano‐based phytochemical efficacy, and in silico pharmacokinetics activities.

Results

Phytochemical Screening

A total of 60 phytochemicals were screened using the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) 2.0 ( https://cb.imsc.res.in/imppat/ ) database and filtered to remove duplicate values [ 23 , 24 ]. After examining each compound's anticancer properties, 25 were found to be active compounds because they demonstrated anticancer properties against at least one form of human cancer (Supporting Information). The structure of all active compounds is drawn in Figure 1 . Common keywords, including specific phytochemicals and each cancer name, were used for searching for words from different databases like Science Direct, PubMed, Scopus, and Google Scholar. Inclusion criteria like Only English‐language, in vitro and preclinical studies were selected, while the studies that repeated the same mechanism, had insufficient methodology, were non‐English, unpublished (e.g., theses, conference papers), or were in silico/review/meta‐analysis without animal models or tumor cell lines were excluded. The bioavailability of our target compounds was determined using the SwissADME server ( http://www.swissadme.ch/ ).

Chemical structures of active compounds having anticancer activity against human malignancies.

In Vitro Anticancer Activities of Active Phytochemicals

In vitro, chemotherapeutic studies of active phytochemicals from E. prostrata are crucial for identifying potential anticancer agents. This medicinal plant is known for its rich bioactive compounds, which exhibit promising cytotoxic effects against cancer cells. By investigating these phytochemicals in controlled laboratory settings, researchers can evaluate their efficacy, mechanism of action, and safety profiles. These studies provide essential data, paving the way for the development of novel, plant‐based chemotherapeutic drugs with fewer side effects and better therapeutic outcomes. This contributes significantly to the advancement of cancer treatment strategies. The summary of chemotherapeutic activities, like cellular and molecular insight of active compounds, is displayed and tabulated in Figure 2 and Table 1 .

Phenolic Acids

3,4‐Dihydroxybenzoic Acid

A naturally occurring substance called 3,4‐dihydroxybenzoic acid is present in E. prostrata leaves. It is also known as protocatechuic acid (PCA), which has shown potential anticancer effects in various cancers. Buskaran and colleagues in vitro research showed that 100 μg/mL of PCA caused the HepG2 cell line to undergo late programmed cell death. This was connected with depolarization of mitochondrial inner membrane potential, halt in the cell cycle, and heightened production of reactive oxygen species (ROS) [ 27 ]. In a distinct study led by M. C. Yin and colleagues, the compound PCA (2‐8 μmol/L) demonstrated various advantageous outcomes in cervix, breast, and prostate cancer cells. These outcomes encompassed a decline in mitochondrial inner membrane potential, a reduction in Potassium‐Sodium Adenosine Triphosphatase (K+, Na+‐ATPase) activity, an augmentation in caspase‐8, 3 activities, an escalation in DNA disintegration, alongside a decrement in the generation of Interleukin‐6 (IL‐6), Vascular Endothelial Growth Factor (VEGF), Intercellular Adhesion Molecule‐1 (ICAM‐1), and Interleukin‐8 (IL‐8), all of which serve as indispensable elements in the proliferation and advancement of cancer [ 28 ]. Yuliana and colleagues discovered that PCA (25 and 50 μg/mL) has the potential to mediate a form of pro‐inflammatory cell death known as pyroptosis via upregulation of the levels of caspase‐1 and caspase‐7 expression [ 29 ]. According to Tseng et al., when leukemia cancer cells (HL‐60) were treated with PCA (2 mM for 9 h), they exhibited DNA fragmentation, which is inter‐nucleosomal and caspase‐mediated cell death evidenced by morphological changes [ 30 ]. Tsao and colleagues noted that by suppressing the expression of p‐focal adhesion kinase, p‐JNK, and p‐p38, the application of PCA treatments at concentrations ranging from 2 to 8 mM resulted in reduced cell proliferation and diminished disparity in electrical charge across the mitochondria's inner membrane in H3255, Calu‐6, and A549 lung cancer cells [ 31 ]. Consistent with findings from Xie and colleagues, treatment with 5–0 μM PCA markedly upregulated the levels of LC3‐II protein and induced the generation of GFP‐LC3 puncta, which are related to autophagy in A2780, SKOV‐3, and OVCAR‐3 ovarian cancer cells [ 32 ]. An additional investigation by Lin and co‐researchers revealed that as protocatechuic acid at a dose of 2 mM impedes cancer cell metastasis by targeting the Nuclear Factor‐kappa B (NF‐kB)/Ras/Protein kinase B (Akt) pathway and suppressing the production of Matrix Metalloproteinases (MMPs)‐2 in skin cancer cells (B16/F10) through the activation of Ras homolog gene family member B (RhoB) [ 33 ].

4‐Hydroxybenzoic Acid

4‐Hydroxybenzoic acid, sometimes called p‐hydroxybenzoic acid (PHBA), is a naturally occurring phenolic chemical made from benzoic acid, which is present in E. prostrata .

In their research, Wang et al. observed that PHBA (0–40 mg/mL, 24 h) triggers programmed cell death, halts the cell‐division cycle, enhances the HIPK2/p53 pathway while inhibiting the HDAC6 pathway in MCF‐7 estrogen receptor‐positive cells [ 34 ]. As indicated by Seidel and colleagues, PHBA suppresses the propagation, colony development, and spheroid viability of PC‐3 and LNCaP tumor cells by reducing HSP90a levels as well as elevating its acetylation [ 35 ]. Sannino and team illustrated that 1 μg/mL of PHBA in lung cancer cells induces pyroptosis and diminishes proliferation by inducing IL1β, IL18, and caspase‐1 gene expression, which are related to pyroptosis and immune reactions [36]. Additionally, Seidel – disclosed that in K‐562 leukemia cancer cells, 4‐hydroxybenzoic acid (100 μM) boosts protein acetylation, leading to increased programmed cell death and halting the cell‐division cycle through hyper‐acetylation of histone and non‐histone proteins. Furthermore, this natural compound hinders the function of p21, cyclin E, and CDKN1A, which are crucial in regulating the cell division cycle [ 37 ].

Ascorbic Acid

Ascorbic acid, frequently designated as vitamin C, is a hydrophilic vitamin integral to various biological functions and may significantly impact the prevention and management of cancer. Research by Choi and colleagues showed that ascorbic acid induces apoptosis and enhances autophagosome production in breast carcinoma cells (HCC‐38 and SKBR3) by reducing mTOR phosphorylation and increasing Beclin1 and ATGs [ 38 ]. Research by Ganash et al. revealed that colon cancer cells (HCT 116) trigger apoptosis, reduce cell viability, and raise LDH levels [ 39 ]. Similarly, Roomi et al. demonstrated that bladder carcinoma cells (T‐24) diminish invasiveness by downregulating matrix metalloproteinase‐2 and 9 [ 40 ]. Wu – highlighted in their study that in cervical cancer cells (HeLa), ascorbic acid induces DNA damage and apoptosis, inhibits cell growth and multiplication by augmenting γH2A x and superoxide dismutase‐1, and reducing Nrf2 [ 41 , 42 , 43 ]. Furthermore, Gao et al. reported that esophageal cancer cells (Eca‐109) induce apoptosis through caspase‐3 and 9 activation and p38 upregulation [ 44 ]. Wan and colleagues found in liver cancer cells (Huh7 and Hep3B) that ascorbic acid stimulates apoptosis, inhibits metastasis, and decreases colony formation by increasing H 2 O 2 levels [ 45 ]. Additionally, Vuyyuri et al. determined that lung tumor cells (H1299, H661, and A549) heighten apoptosis and DNA fragmentation by increasing ROS and decreasing PARP activity [ 46 ]. Another investigation by Xia and colleagues concluded that in myeloma cancer cells (CD138+), ascorbic acid induces apoptosis and prevents tumor formation through AIF1 upregulation [ 47 ]. In line with Ohwada and colleagues, oral cancer cells (HSC‐4) foster apoptosis and reduce cell growth by elevating H 2 O 2 and O 2 − [ 48 ]. A study by Amiri and colleagues demonstrated that in prostate adenocarcinoma cells (PC3 and DU145), ascorbic acid inhibits angiogenesis, cell growth, and metastasis while promoting apoptosis by downregulating CXCR4, CXCR7, α4, α5, β1 integrins, ki‐67, and VEGF [ 49 ]. Finally, Wang and colleagues discovered that in thyroid carcinoma cells (8505C and C643), ascorbic acid induces ferroptosis, ferritinophagy, and decreases cell growth by lowering GPX4 levels [ 50 ]. These investigations collectively emphasize the varied anticancer impacts of ascorbic acid, operating through diverse molecular pathways, such as apoptosis induction, proliferation, and metastasis inhibition, oxidative stress modulation, and key signaling pathways regulation, highlighting its potential as an adjunctive strategy in cancer therapeutic approaches.

Flavonoids

Apigenin

Apigenin, a flavonoid compound, is present in the foliage of E. prostrata , demonstrating potential chemopreventive effects by lowering oxidative stress and inflammation, along with other physiological pathways. The research conducted by Lee and colleagues revealed that apigenin (20–40 μM) inhibits the translation of snail and N‐cadherin in MDA‐MB‐231 breast tumor cell lines, resulting in decreased cell migration and invasiveness [ 51 ]. Similarly, research by Chen and colleagues illustrated that apigenin affects gastric carcinoma cells by impeding cell proliferation, facilitating programmed cell death, and diminishing mitochondrial electrochemical gradient, achieved by the regulation of Bcl‐2 at concentrations of 1–10 μg/mL of apigenin and the modulation of caspase‐3 and Bax [ 52 ]. Investigation in colon cancer, as conducted by K. Banerjee and M. Mandal, indicated that apigenin (3.125 and 1.56 µM) induces programmed cell death, showcases antiproliferative properties, elevates ROS levels, reduces RNS, and enhances mitochondrial transmembrane potential and superoxide production in carcinoma cells (HCT‐15) [ 53 ]. Xia and team's research demonstrated that apigenin (0–50 mM) displays anti‐invasion properties by downregulating IL‐1β, ERK1/2, uPAR, AP‐1, NF‐kappa B, and JNK kinase in T24 bladder carcinoma cells [ 54 ]. The examination of cervical cancer (HeLa and C33A cells) revealed that apigenin (50 µM) diminishes cell viability, halts cell cycle progression, promotes epithelial‐to‐mesenchymal transition, fosters mitochondrial‐mediated programmed cell death, and downregulates β1‐FAK and PI3K/AKT signaling [ 55 ]. An experimental analysis by Qiu et al. in esophageal cancer (Eca‐109, Kyse‐30 cells) exhibited that at concentrations of 0.3, 1, 3, and 10 µM, it inhibits angiogenesis, induces caspase‐mediated cell death through the downregulation of IL‐6 and VEGF, while upregulating caspase‐8 and C‐PARP [ 56 ]. Yang and colleagues discovered that apigenin (10, 20, and 40 μM) augments regulated cell death, triggers autophagy, reduces cell growth, and enhances cell demise by downregulating the Phosphoinositide 3‐kinase/Akt/mammalian target of rapamycin pathway in HepG2 liver carcinoma cells [ 57 ]. Furthermore, it mediates programmed cell death, diminishes cell survival and mitochondrial voltage gradient, and increases DNA damage in lung melanoma (H460) by modulating various molecular targets, including Bid, procaspase‐8, AIF, Cytochrome c, GRP78, GADD153, and Ca2+, as reported by Lu et al. [ 58 ]. An in vitro study executed by Jayasooriya et al. demonstrated that in leukemia cancer (U937, THP‐1, and HL60 cells), apigenin (100 μM) reduces telomerase activity, promotes programmed cell death, and induces a halt in cell‐division cycle progression by lowering hTERT [ 59 ]. In myeloma cancer (U266 and RPMI 8226), it (10, 30, 60, 90 μM) triggers programmed cell death by inhibiting Cdc37 phosphorylation, CK2 kinase activity, and STAT3 signaling, while upregulating RIP1, Src, Raf‐1, and Cdk4 and downregulating Mcl‐1 and XIAP [ 60 ]. Maggioni et al. reported that apigenin at doses of 50 and 100 µM stimulates programmed cell death and causes a halt in cell‐division cycle progression by lowering cyclin D1 and E and CDK1 in oral cancer (SCC‐25 cells) [ 188 ]. Li and colleagues findings demonstrated that in ovarian cancer (A2780 cells), apigenin (20 and 40 µM) restrains proliferation, decreases tumor growth, and induces programmed cell death by downregulating Id1 by activating ATF3 [ 171 ]. Another study by Shukla et al. on PC‐3 and 22Rv1 prostate tumor cells suggested that it (2.5, 5, 10, and 20 μM) modulates the IKKα pathway to enhance caspase‐mediated cell death, reduce invasiveness, cause a halt in cell‐division cycle progression, and decrease proliferation [ 172 ]. Bridgeman et al. studied skin cancer (308 keratinocyte cells) and discovered that apigenin at a level of 25 μM causes a decrease in cell growth, induction of a halt in cell‐division cycle progression, and promotion of autophagy via downregulating mTOR signaling [ 174 ]. Lastly, Kim and colleagues demonstrated that phytochemicals (10, 20, 40, and 80 μM) increase caspase‐mediated cell death in thyroid adenocarcinoma cells (8505C, TPC1, and CAL62) by altering molecular targets such as c‐Myc, p38, and p53 [ 176 ]. These studies collectively highlight apigenin's diverse anticancer effects across multiple cancer types, acting via various molecular pathways, including programmed cell death induction, halt in cell‐division cycle progression, and inhibition of proliferation and invasion.

Luteolin

Luteolin, a flavonoid compound found in E. prostata leaves, demonstrates significant anticancer properties across various cancer types through diverse mechanisms. In breast cancer, luteolin inhibits cancer stem cell (CSC) properties by suppressing stemness‐related factors, CD44, ABCG2, and aldehyde dehydrogenase‐1 activity while also increasing TRX1 expression and decreasing reactive oxygen species generation [ 177 ]. In an in vitro study conducted by Iida and colleagues, luteolin increased TRX1 expression while decreasing intracellular reactive oxygen species generation, reduced cell survival, and triggered G2/M cell‐cycle arrest, p21 upregulation, and phospho(p)‐S6 downregulation, all of which are downstream of mTOR signaling [ 175 ]. Esophageal cancer causes apoptosis in Eca109 cells by modulating cyclin D1, survivin, c‐myc, and p53 expression [ 179 ]; according to Ren and colleagues, luteolin and oxaliplatin combined reduced SGC‐7901 cell growth and promoted apoptosis by changing cell‐cycle proportions and activating Cyt c/caspase signaling [ 189 ]. Luteolin's effects extend to other cancer types as well. Clear cell renal cell carcinoma (ccRCC) increases HO‐1 expression, leading to ferroptosis through Fenton reaction, GSH depletion, and lipid peroxidation [ 180 ]. For liver cancer, luteolin (5‐10 μM) enhances cytotoxicity and apoptosis in Hep3B cells through p53‐dependent cell death and p21 induction [ 181 ]. In lung cancer, particularly when combined with apigenin, luteolin decreases cell growth, induces apoptosis, and suppresses IFN‐induced PD‐L1 expression by inhibiting STAT3 phosphorylation [ 182 ]. Additionally, Deng et al. summarized that luteolin suppressed leukemic cell line growth via cell death and cell migration; however, overexpression of RSK1 reduced this effect. A similar impact was observed when RSK1 expression was reduced on MOLM‐13 and Kasumi‐1 leukemic cells [ 183 ]. Luteolin (20 µM) in multiple myeloma suppresses RPMI 8826 cell growth and enhances autophagy and apoptosis through caspase3 and LC3 II/I activation [ 185 ]. For ovarian cancer, it decreases ovarian cancer stem cell (OCSC) proliferation and self‐renewal via IL‐6/STAT3 signaling deactivation [ 186 ]. Han and colleagues explained that luteolin induced apoptosis and suppressed cell growth via the overexpression of miR‐301 in PC3 and LNCaP cells [ 187 ]. Finally, Hwang et al. stated that luteolin (1–5 μM) increased cell survival by activating MMPs and decreasing UVA [ 61 ]. These findings collectively highlight luteolin's potential as a versatile anticancer agent, acting through various mechanisms, including apoptosis induction, halt in cell‐division cycle progression, autophagy modulation, and regulation of key signaling pathways across multiple cancer types. However, more research is needed to fully elucidate its clinical potential and optimize its use in cancer treatment strategies.

Orobol

Orobol is a rare isoflavone found in extremely small concentrations in soybeans, which can be produced during soybean fermentation or through metabolism in the body. Structurally related to genistein, the most common soy isoflavone [ 62 ], orobol has demonstrated potential anticancer properties in different types of cancer despite its rarity. Orobol has shown remarkable effects on breast cancer (MCF‐7 cells). It drastically reduces cell growth and viability while increasing cytotoxicity in these cells at a particular dose [ 63 ]. These findings denote that orobol could be a promising agent for breast cancer treatment. In ovarian cancer, orobol has exhibited consequential anticancer effects on human ovarian carcinoma 2008 cells and 2008/C13*5.25 (C13) cells. Its mechanism of action in these cells involves activating apoptosis mediated by the caspase cascade. Additionally, Bcl‐2 is an antiapoptotic protein whose expression is decreased by orobol, further promoting cell death. Moreover, it reduces the amounts of matrix metalloproteinases (MMPs), which are critical for the invasion and spread of cancer cells, suggesting that orobol may potentially prevent cancer spread [ 64 ].

These findings collectively indicate that the anticancer mechanisms of orobol include suppression of cell growth and proliferation, cytotoxicity induction, apoptosis via the caspase cascade, downregulation of antiapoptotic proteins, and decrease of MMPs. While these results are promising, it is crucial to remember that there is still little study on orobol, likely due to its rarity in nature. Further studies are needed to fully elucidate its anticancer potential, investigate its effects on other cancer types, and determine its potential for clinical applications. Additionally, research into methods of increasing orobol production or synthesis could be valuable for expanding its study and potential use in cancer treatment.

Diosmetin

Diosmetin, a flavonoid compound naturally found in E. prostrata , has demonstrated significant anticancer properties across various cancer types through multiple mechanisms. In breast cancer, Wang et al. reported that diosmetin exhibits cytotoxic effects on MDA metastasis breast carcinoma cell 231, reducing cell viability, increasing ROS accumulation, and enhancing the halt in cell‐division cycle progression. It also modulates critical proteins involved in apoptosis and cell cycle regulation, downregulating Bcl‐2 and Cyclin D1 while upregulating p53, Bax, caspase 3, and cleaved caspase 9 [ 65 ]. In colon cancer, Koosha et al. showed that diosmetin induces apoptosis by activating Fas and Bax, releasing cytochrome c from mitochondria, inhibiting cell growth, and blocking NF‐κB translocation in HCT‐116 cells in a dose‐dependent manner [ 66 ]. Qiu et al. demonstrated that in renal cancer ACHN cells, diosmetin increases P53 mRNA expression, decreases phosphorylation of PI3K/AKT, induces apoptosis, and reduces cell survival [ 67 ]. For liver cancer, Ma et al. reported that diosmetin induces a halt in cell‐division cycle progression in the G2/M phase, modulates various apoptosis‐related proteins, and inhibits cell growth in HepG2 and HCC‐LM3 cells [ 68 ]. Chen and colleagues found that diosmetin synergistically suppresses NSCLC cells when combined with paclitaxel through PI3K/Akt/GSK‐3β/Nrf2 pathway disruption and ROS accumulation [ 69 ]. In breast cancer, Roma et al. demonstrated that diosmetin induces apoptosis through increases in caspases 8 and 3/7, as well as TNF, which is dependent on estrogen receptor expression [ 70 ]. Zhao et al. demonstrated diosmetin's effects on ovarian tumor cells, suppressing proliferation, migration, and invasion while inducing apoptosis and modulating the Nrf2 pathway [ 71 ]. Under a study by Oak et al., it was summarized that diosmetin inhibits cell growth and induces apoptosis while inhibiting XIAP and enhancing PARP and caspase expression, diminishes cyclin D1, Cdk2, and Cdk4 expression levels, downregulates c‐Myc and Bcl‐2 expression, and upregulates Bax, p27Kip1 and FOXO3a protein development in prostate cancer PC‐3 cell lines in a dose‐dependent manner [ 72 ]. Finally, Choi and colleagues showed that diosmetin inhibits tumor progression and metastasis by increasing cell death, decreasing angiopoietin‐2 in HUVECs, and activating caspases when they induced apoptosis in B16F10 mouse melanoma cells [ 73 ]. These studies collectively highlight diosmetin's potential as a versatile anticancer agent, acting through various mechanisms, including apoptosis induction, halt in cell‐division cycle progression, ROS modulation, and inhibition of key signaling pathways across multiple cancer types.

Pratensein (PTS)

PTS, an O‐methylated isoflavone derived from Trifolium pratense L., has powerful antioxidant and anti‐inflammatory qualities [ 74 ]. In breast carcinoma cells (MCF‐7), prateasein (2.5–200 µg/mL) causes apoptosis by upregulating the genes for caspase‐3, p53, and Bax, while downregulating the expression of bcl2 [ 75 ].

Cynaroside

Cynaroside is a naturally occurring flavonoid compound detected in E. prostrata that has shown promising anticancer activity through multiple mechanisms. Shao et al. demonstrated that cynaroside inhibits migration and enhances programmed cell death in HeLa cells by reducing MMPs and upregulating Fas, Bax, p53, phosphorylated p38, phosphorylated JNK, and activated PARP while downregulating Bcl‐2 and phosphorylated‐mTOR signaling pathways, activated caspase‐3 and caspase‐8 [ 76 ]. An in vitro investigation conducted by Ji and colleagues demonstrated that cynaroside promotes programmed cell death and diminishes cellular proliferation, migration, and invasion in gastric adenocarcinoma cells by suppressing the MET/AKT/mTOR signaling pathway through downregulation of mammalian target of rapamycin, P70S6K, and AKT phosphorylation levels [ 77 ]. Nho and colleagues found that cynaroside (10 μM) reduced the cisplatin‐driven apoptotic pathway, impaired mitochondrial function, and activated caspase‐3 in HK‐2 cells [ 78 ]. Subsequent research has demonstrated that cynaroside also exhibits considerable effects on various other malignancies. Hwang et al. proved that cynaroside mediates apoptosis as well as regulates cell cycles through G2‐M phase arrest, reactive oxygen species generation, and JNK activation in hepatocarcinoma HepG2 cell lines [ 79 ]. Zhou and colleagues reported that cynaroside mediates autophagic degradation in nonsmall cell lung cancer cells, linked to the formation of autophagic vacuoles, degradation of p62, and overexpression of Beclin‐1 and LC3‐II, with ROS influencing the signaling cascade as an upstream mediator [ 80 ]. Velmurugan et al. summarized that cynaroside prevents cell growth, movement, and tissue infiltration, increases apoptosis, and reduces metastasis by downregulating MMP2 and p38 phosphorylation [ 81 ]. These findings collectively highlight cynaroside's potential as an anticancer agent across various cancer types. Its diverse mechanisms of action include the induction of apoptosis, inhibition of cell growth and migration, modulation of cell cycle progression, and activation of autophagy. The compound's ability to target multiple signaling pathways, such as MET/AKT/mTOR and p38, underscores its promise as a multifaceted therapeutic agent in cancer treatment strategies. Further research is needed to fully elucidate its clinical applications and potential synergistic effects with other treatments.

Demethylwedelolactone

Demethylwedelolactone, a naturally occurring coumestan isolated from E. prostrata , has demonstrated promising anticancer properties, particularly in breast cancer. A study by Lee and colleagues revealed that demethylwedelolactone (DWEL) exhibits significant anti‐invasive effects on human MDA metastasis breast carcinoma cell 231. The compound was detected to suppress anchorage‐independent evolution, suppress cell motility and invasion, reduce the activity and expression of matrix metalloproteinases (MMPs), and inhibit the IκB‐α/NFκB and MEK/ERK signaling pathways. Importantly, in vivo studies using nude mice showed that DWEL suppressed metastasis and lung colonization of tumor cells [ 82 ]. These findings suggest that demethylwedelolactone exerts its anticancer effects through multiple mechanisms, targeting different aspects of cancer cell biology, including growth, invasion, and metastasis. While these results are promising and highlight the potential of demethylwedelolactone as an anticancer agent, particularly for breast cancer treatment, further research is needed to fully elucidate its mechanisms of action, evaluate its efficacy against other cancer types, and assess its potential for clinical applications.

Wedelolactone

7‐methoxy‐5,11,12‐trihydroxy‐coumestan is known as wedelolactone, a naturally occurring substance primarily produced by plants in the Asteraceae family, with important sources being E. prostrata and Wedelia chinensis [ 83 ]. Wedelolactone functions as an inhibitor of proteasome activity in MDA metastasis breast carcinoma cells 231 and 468, T47D breast carcinoma cells, particularly causative enzyme‐like, chymotrypsin‐like, and trypsin‐like activities. By controlling Bax, p21, p27, and p53 in a dose‐dependent way, it raises polyubiquitinated proteins and causes apoptosis [ 84 ]. In prostate cancer cell lines (LNCaP, PC3, and Balb/c nude mice), wedelolactone induces apoptosis and prevents invasion and cell migration by reducing c‐Myc mRNA and the expression of survivin, TMPRSS2, ADAMTS1, cyclin D1, PCNA, Aurora kinase, and Gemin4, while upregulating ATF3 [83]. In ovarian cancer (SKOV‐3 cells), wedelolactone (2.5 μM) suppresses cell progression by downregulating the expression of ER‐positive, Cyclin D1, TERT, and E2F1 [ 85 ]. For skin cancer (MV3 cells and nude mice), Wedelolactone decreases Bcl‐2 and increases Bax and p21 to cause apoptosis. Additionally, it inhibits cell growth, migration, and invasion, upregulating AMPK and downregulating cyclin D and AKT [ 86 ]. These findings emphasize wedelolactone's potential as a multi‐target anticancer drug; nevertheless, more study is needed to fully understand its mechanisms and possible therapeutic uses.

Triterpenoids/Triterpenes

Alpha‐Amyrin

Alpha‐amyrin, a pentacyclic triterpenoid, has exhibited noteworthy biological effects as a ligand for nuclear receptors, enzyme inhibitors, GPCRs, and protease inhibitors. Its anticancer properties have been documented in various cancer types [ 87 ]. Lima et al. reported that alpha‐amyrin (2.35 µM) induced apoptosis in MCF‐7 cells by reducing Caspase‐3 and ACE activity while elevating TNF‐α levels, indicating potential anti‐inflammatory effects [ 88 ]. In the context of colon cancer, alpha‐amyrin (10 µM) mitigated inflammation, facilitated cell death, and decreased cell survival in HT‐29 cells by upregulating COX‐2 expression [ 89 ]. Regarding gastric cancer, alpha‐amyrin (92.15 µM) displayed cytotoxic properties against SNU‐16 cells, leading to apoptosis‐induced cell growth and multiplication by activating caspase‐3, 7, 8, and 9 [ 90 ]. Park and colleagues demonstrated that alpha‐amyrin (15.45 ± 6.82 μM) induced apoptosis in A549 lung tumor cells and triggered G1 phase halt in cell‐division cycle progression through enhanced Bax protein expression, inhibition of Bcl‐2, and initiation of caspase‐3 cleavage [ 91 ]. In leukemia, Barros et al. explored alpha‐amyrin (1.8–3 µM) and showed cytotoxic effects on HL‐60 cells by inducing apoptosis via modulation of Caspases‐3/7 activity and inhibition of cell growth [ 92 ]. Dinku et al. highlighted that alpha‐amyrin (21.96 µM) suppressed proliferation and cell growth in A2780 ovarian adenocarcinoma cells without specifying the precise molecular mechanisms [ 93 ]. Lastly, T. D. Viet, T. D. Xuan, and L. H. Anh outlined that alpha‐amyrin (125.55 µM) impacted melanoma cells by diminishing inflammation and proliferation, correlated with increased generation of reactive oxygen species and reactive nitrogen species (ROS/RNS) [ 94 ]. These investigations collectively underscore the potential of alpha‐amyrin as an effective anticancer agent in diverse cancer types. Its varied mechanisms of action encompass apoptosis induction, inhibition of cell growth, modulation of signaling pathways, regulation of caspase function, adjustment of Bcl‐2 family proteins, and initiation of oxidative stress. This comprehensive approach emphasizes the promise of alpha‐amyrin as a versatile anticancer compound, necessitating further exploration of its therapeutic prospects in cancer management.

Beta‐Amyrin

Beta‐amyrin, a pentacyclic triterpene naturally present in different plant species, has exhibited a broad spectrum of biological and pharmacological attributes, encompassing potential anticancer properties in various types of cancer [ 95 ]. Within the context of breast carcinoma, Lima et al. documented that beta‐amyrin (2.48 µM) induced apoptosis in MCF‐7 cells by inhibiting Caspase‐3 and ACE activity while concurrently elevating TNF‐α levels, indicating plausible anti‐inflammatory effects [ 88 ]. Correspondingly, in colon cancer, the application of beta‐amyrin (10 µM) led to decreased inflammation, stimulated cell death, and reduced cell survival in HT‐29 cells through upregulation of COX‐2 expression [ 89 ]. A study by A. You, M. Be, and I. revealed that beta‐amyrin triggered apoptosis in A498 renal carcinoma cells by arresting the cell cycle at the G2/M checkpoint and inhibiting cell growth [ 96 ]. In the sphere of liver cancer, S. Wen, D. Gu, and H. Zeng provided evidence of beta‐amyrin's noteworthy anticancer activity against Hep‐G2 cells, with an IC50 value of 25 µM [ 97 ]. This compound instigated apoptosis and G2/M halt in cell‐division cycle progression in a manner dependent on dosage while activating the p38 and JNK signaling pathways. Furthermore, Park and collaborators highlighted that beta‐amyrin (10.33 ± 7.4 µM) induced G1 phase halt in cell‐division cycle progression and apoptosis in A549 lung adenocarcinoma cells by upregulating Bax protein expression, downregulating Bcl‐2, and initiating caspase‐3 cleavage [ 91 ]. In the domain of leukemia, beta‐amyrin (1.8–5 µM) prompted apoptosis in HL‐60 and U937 cells by inhibiting Bcl‐2, initiating caspase 3 cleavage, and impeding cell growth and proliferation [ 98 ]. Lastly, Victor et al. scrutinized the impact of beta‐amyrin (5 µM) in prostate cancer, observing a reduction in cell growth of PC3 cells through inhibition of proliferation and attenuation of inflammation [ 99 ]. These investigations collectively underscore the potential of beta‐amyrin as an anticancer agent in diverse cancer types. Its multifaceted mechanisms involve apoptosis induction, halt in cell‐division cycle progression, suppression of cell growth, and modulation of various signaling pathways. The compound's capacity to target numerous facets of cancer cell biology emphasizes its promise as a potential therapeutic agent in cancer treatment modalities, necessitating further exploration regarding its clinical utility.

Eclalbasaponin I

Eclalbasaponin I, a compound derived from E. prostrata , has demonstrated promising antitumor activities through various mechanisms. This compound has been shown to inhibit cancer cell growth, induce apoptosis, and inhibit angiogenesis while potentially exerting immunomodulatory effects. A notable study by Liu et al. revealed that eclalbasaponin I exhibit a synergistic effect with ethanol in inhibiting the proliferation of hepatoma cells (SMMC‐7721) in a dose‐dependent manner. This synergistic action suggests that eclalbasaponin I could potentially enhance the efficacy of other cancer treatments [ 102 ]. However, it is important to note that the current research is limited, focusing primarily on liver adenocarcinoma cells. Further studies are necessary to validate these findings in other liver cancer cell lines, investigate its effects on different cancer types, elucidate the specific molecular mechanisms underlying its anticancer activities, evaluate its in vivo efficacy and safety, and explore potential synergistic effects with other anticancer treatments. While the initial results are promising, more comprehensive research is required to fully understand eclalbasaponin I's potential as an anticancer agent and determine its possible role in cancer treatment strategies.

Eclalbasaponin II

Eclalbasaponin II, a saponin compound isolated from E. prostrata , has demonstrated significant anticancer properties, particularly in ovarian and endometrial cancer. A study by Cho and colleagues found that eclalbasaponin II exhibits potent cytotoxicity against multiple ovarian and endometrial cancer cell lines, surpassing the effects of its related compounds. The compound induces both apoptotic and autophagic cell death in SKOV3 and A2780 ovarian carcinoma cells, as evidenced by Annexin V staining and increased acidic vesicular organelle content. Mechanistically, eclalbasaponin II activates JNK and p38 signaling pathways while inhibiting the mTOR pathway, with these effects occurring in a dose‐dependent manner. Notably, the study found an intricate interplay between autophagy and apoptosis, as inhibition of autophagy by BaF1 suppressed eclalbasaponin II‐induced apoptosis. These findings highlight eclalbasaponin II's potential as a promising anticancer agent, capable of targeting multiple cell death mechanisms and signaling pathways [ 103 ]. However, further research is necessary to fully elucidate its mechanisms of action, evaluate its efficacy in other cancer types, and assess its potential for clinical applications.

Ursolic Acid (UA)

Many medicinal plants contain UA, a pentacyclic triterpenoid that has been shown to have anticancer effects on a variety of cancer forms. UA increases apoptosis and decreases migration, proliferation, and cell survival in breast adenocarcinoma cells (T47D, MCF‐7, and MDA metastasis breast carcinoma cell 231) and suppresses inflammatory cytokines by regulating targets like PI3K, AKT, GSK, and NF‐κB [ 104 ]. For bladder cancer, UA inhibits pAkt1, NF‐κBp65, and caspase‐3 to cause cell growth inhibition and death in T24 cells [ 105 ]. In colorectal cancer cells (SW480, LoVo), UA inhibits proliferation, viability, and migration while inducing apoptosis through pathways involving MMP9, Akt, ERK, and NF‐kB [ 106 ]. UA also causes apoptosis in cervical cancer (HeLa cells) by affecting cytochrome c, caspases, and ERK1/2 phosphorylation [ 107 ]. Lee discovered that in esophageal squamous cell carcinoma (ESCC) cells (TE‐8 and TE‐12), UA reduced cell viability, migration, and invasion through dose‐dependently upregulating molecular targets like LC3‐II, ROS, and p‐Akt and downregulating p62, Akt‐mTOR, and protein kinase B (Akt) signaling [ 108 ]. UA's anticancer effects extend to other cancer types as well. In kidney cancer (A498 cells), UA induced NLRP3, IL‐1, and caspase‐1 levels while inhibiting cell growth and invasiveness. MMP2 expression was also decreased in a dose‐dependent way [ 109 ]. UA promotes apoptosis, halts cell‐division cycle progression, and reduces liver cancer (SMMC‐7721 cells) development by altering the expression of p53, Bax, and Bcl‐2 [ 111 ]. In A549, H3255, and Calu‐6 lung cancer cell lines, UA inhibits proliferation, migration, and invasion, producing DNA damage [ 112 ]. UA elicits apoptosis in a variety of leukemia cells and suppresses tumor development in mice by targeting ROCK1, PARP, and caspases [ 190 ]. In myeloma cells (U266, KBM‐5), UA exhibits proapoptotic effects and inhibits cell growth and multiplication by regulating interleukin‐6 and STAT3 activation [ 113 ]. For oral cancer (Ca922, SCC2095 cells), UA enhances autophagy and reduces proliferation by modulating the Akt/mTOR/NF‐B pathway [ 114 ]. W. Lin and H. Ye discovered that 35 µM of UA causes a halt in cell‐division cycle progression, apoptosis, and changes in Bax, G2/M phase, Bcl‐2, MMP, ROS, PI3K, AKT, and AKT phosphorylation in SKOV‐3 ovarian cancer cells [ 191 ]. UA reduced cell growth and multiplication, induced apoptosis, and changed Survivin, caspase‐3, Bcl‐2, Bcl‐xL, PI3K, mTOR signaling, and phosphorylation of Akt in a dose‐dependent way in an in‐vitro and in‐vivo study using LNCaP and PC‐3 prostate tumor cells and female athymic nude mice [ 115 ]. UA at 10 and 20 μM doses in skin cancer (M4Beu cells) triggered apoptosis and impacted bax, bcl‐2, caspase‐3, and mitochondrial potential difference [ 116 ]. Furthermore, X. Cao and Q. He found that UA suppresses the growth, migration, and invasion of thyroid cancer cell lines TPC‐1 and B‐CPAP by downregulating CXCR4, CXCR7, and CXCL12 in a dose‐dependent manner [ 118 ].

Although further investigation is required to completely understand its processes and its clinical uses, these findings demonstrate UA's promise as a therapeutic agent in the treatment of cancer.

Oleanolic Acid (OLA)

OLA, a prevalent triterpenoid in plants, has demonstrated significant anticancer potential across multiple cancer types [ 119 , 192 ]. In breast tumor cells (MDA metastasis breast carcinoma cell 231, 4T1‐luc, MCF‐7, and MCF‐10a), OLA (40 μM) suppresses cell growth and promotes apoptosis via regulating multiple genes [ 120 ]. For bladder cancer, OLA (20‐50 μM) causes apoptosis and decreases cell growth in T24 cells via decreasing pAkt, mTOR, S6K, and p‐ERK1/2 while inducing caspase‐3 [ 193 ]. In gastric cancer cell lines (AGS cells and mouse models), OLA prompts autophagy, decreases cell viability, and enhances apoptosis in a dose‐dependent way by altering AKT/PI3K/mTOR signaling and apoptosis‐related proteins [ 121 ]. For liver cancer arrest in HepG2 cells, OLA (30–60 μM) inhibits p‐JNK phosphorylation and p‐p38, which causes apoptosis and cell cycle [ 122 ]. In lung cancer (SPC‐A‐1 cells), OLA (8–16 μM) triggers apoptosis via modifying the Bcl‐2, Bad, and Bax proteins [ 123 ]. OLA also has anticancer effects on other cancer types. In leukemia, OLA (30‐32 μmol/L) inhibits cell growth in different cell lines [ 194 ]. For prostate cancer cell lines (DU145, PC‐3, and LNCaP cells), OLA promotes a halt in cell‐division cycle progression apoptosis and reduces cell survival and proliferation by altering multiple molecular targets, including CDK4, cyclin D1, and PI3K/AKT signaling [ 125 ]. In skin cancer (A375SM and A375P cells), OLA (60–100 μM) enhances apoptosis and reduces cell survival by modulating NF‐κB pathway signaling [ 126 ]. For thyroid carcinoma (SW579 cells), OLA (20–40 μmol/L) decreases migration, colony formation, and invasion while causing cell death through various mechanisms [ 127 ]. OLA downregulates TNF‐α, PRL‐3, NF‐κB p65, E‐cadherin, and IL‐6 in ovarian cancer (SKOV 3 cells) to prevent cell growth, movement, and tissue infiltration [ 128 ]. These findings indicate the broad anticancer capability of oleanolic acid across multiple cancer types, though Further investigation is required to comprehend its mechanisms and possible therapeutic uses completely.

Terpenes/Sesquiterpenes—Beta‐Farnesene

Beta‐farnesene, a natural sesquiterpene hydrocarbon found in E. prostrata , has shown potential anticancer properties, particularly in breast cancer. Afoulous et al. demonstrated that β‐farnesene at a dose of 21.5 mg/L exhibited increased toxicity, anticancer activity, and anti‐inflammatory properties in MCF‐7 estrogen receptor‐positive cells [ 129 ].

Sterols/Phytosterols

Beta‐Sitosterol

Beta‐sitosterol, a plant sterol structurally similar to cholesterol, has demonstrated potential anticancer properties across various cancer types. In breast cancer, Awad et al. showed that β‐sitosterol induces apoptosis, transforms cell membranes, and suppresses cell growth in MCF‐7 and MDA metastasis breast carcinoma cell 231 by enhancing Fas levels and caspase‐8 activity [ 130 ]. Gu and colleagues found that in colon cancer, β‐sitosterol inhibited HCT116 cell growth, migration, and growth by downregulating the LEF‐1 gene and disrupting the Wnt/β‐catenin pathway [ 131 ]. For cervical cancer, Cheng et al. demonstrated that β‐sitosterol (20 µM) reduced PCNA expression, increased p53 mRNA levels, and decreased HPV E6 transcripts in HeLa cells, suppressing cell growth and enhancing apoptosis [ 132 ]. Zhao et al. reported that β‐sitosterol suppresses proliferation and promotes apoptosis in SGC‐7901 stomach carcinoma cells by damaging DNA and modulating pro‐caspase‐3, bax, and bcl‐2 expression [ 134 ]. In liver cancer, Vo et al. showed that β‐sitosterol induces apoptosis and activates caspase‐3 and ‐9 in HepG2 and Huh7 cells [ 135 ].

Wang et al. found that β‐sitosterol treatment reduced autophagy markers, induced G0/G1 halt in cell‐division cycle progression, and inhibited cell growth in A549 lung tumor cells by decreasing TGF‐β/Smad2/3/c‐Myc pathway proteins [ 136 ]. According to Sook and colleagues, Beta‐sitosterol increased the sub‐G1 apoptotic population, activated caspase‐9 and ‐3, and decreased mitochondrial capacity in U266 cells. It induced ROS production, activated AMPK, ACC, and JNK, and attenuated phosphorylation of AKT and cyclooxygenase‐2, while AMPK inhibitor compound C and JNK inhibitor SP600125 reduced apoptosis [ 137 ]. Han and colleagues observed that β‐sitosterol decreased cyclin B1 and cdc2 levels while increasing p21waf1/cip1 in premalignant and malignant cell lines [ 138 ]. For ovarian cancer, Bae et al. showed that β‐sitosterol induces apoptosis, suppresses proliferation, increases ROS production, and alters Ca2+ influx, inhibiting cell aggregation, growth, and migration [ 140 ]. Finally, Pradhan et al. demonstrated that β‐sitosterol induces apoptosis, decreases cellular viability, and inhibits migration in PC‐3 and DU145 prostate cancer cell lines while decreasing DNMT1 protein content and enzyme activity, and modulating Bcl2, E‐cadherin, and Bax expression [ 141 ]. These studies collectively highlight β‐sitosterol's potential as an anticancer agent across multiple cancer types, acting through various mechanisms, including apoptosis induction, cell cycle disruption, and modulation of key signaling pathways.

Stigmasterol

Stigmasterol, a phytosterol structurally related to cholesterol, is frequently found in several plant sources, including fruits, vegetables, plant oils, soybeans, maize, peanuts, wheat, lentils, and sunflower oils [ 142 ]. This compound has demonstrated anticancer properties across multiple cancer types. In bladder tumor cells, stigmasterol induces apoptosis by affecting molecules, such as p27, Jab1, and caspase‐3 [ 143 ]. Additionally, at dosages of 10.36 and 12.21 μM, it promotes a halt in cell‐division cycle progression in HeLa cells and raises p53 levels [ 144 ]. Stigmasterol suppresses the JAK/STAT signaling pathway in a dose‐responsive way, lowers cell migration, and promotes a halt in cell‐division cycle progression and death in gastric cancer cell lines (SNU‐1 and GES‐1) [ 145 ]. Moreover, stigmasterol increases caspase 8, 9, and Bax expression in liver cancer (HepG2 cells), resulting in a halt in cell‐division cycle progression and death [ 146 ]. The anticancer effects of stigmasterol extend to other cancer types as well. In lung cancer cell lines, stigmasterol (20 μg/mL) downregulates caspase‐3, caspase‐9, and RORC to stop cell growth and induce apoptosis [ 147 ]. It decreases PTKs and EGFRK for oral cancer‐inducing apoptosis in KB/C152 cells [ 148 ]. In ovarian cancer (ES2 and OV90 cells), stigmasterol induces apoptosis, mitochondrial depolarization, calcium modulation, and autophagy through various intracellular signals [ 149 ]. Additionally, in prostate cancer (DU‐145 cells), stigmasterol (5 μM) suppresses cell growth and multiplication by upregulating p53 and downregulating p21 and p27 gene expression [ 151 ]. These results demonstrate the promise of stigmasterol as a therapeutic agent in cancer treatment; nevertheless, more investigation is required to completely comprehend its processes and therapeutic uses.

Fatty Acids

Linoleic Acid (LA)

LA, a polyunsaturated omega‐6 fatty acid, demonstrates diverse and sometimes contradictory effects on various cancer types. In breast cancer, Diaz‐Aragon et al. showed that LA induces cell migration and invasion in MDA metastasis breast carcinoma cell 231 through increased PLD activity, mediated by FFAR1, FFAR4, and EGFR activities [ 150 ]. Conversely, in prostate cancer, Oh and colleagues found that LA suppresses cell growth and promotes cell death in TSU‐Pr1 cells by diminishing DNA synthesis and IRS‐1 levels, blocking the IGF‐IR signaling pathway [ 152 ]. Song and colleagues also reported the anticancer and antiproliferative effects of LA in LNCaP prostate adenocarcinoma cells, affecting PKC isomer abundance in a dose‐dependent manner [ 195 ]. In colon cancer, Q. Liu and colleagues demonstrated that LA treatment of CT26 cells results in lower oxidative phosphorylation, glycolysis, energy production, and reduced Pgc1 and MycC expression [ 153 ]. The effects of LA vary significantly in other cancer types. Matsuoka and colleagues found that LA enhances metastasis and cellular invasion of OCUM‐2MD3 gastric tumor cells, dependent on ERK phosphorylation and COX‐1 activity [ 196 ]. In lung cancer, Mouradian and colleagues showed that LA supplementation boosts cellular proliferation in A549 cells, enhances cyclooxygenase activity, increases prostaglandin E2 levels, and elevates matrix metalloproteinase and transforming growth factor alpha levels [ 197 ]. Contrastingly, in leukemia, Lui and colleagues reported that LA suppresses the growth of murine myeloid leukemia WEHI‐3B‐JCS cells in a dose‐dependent manner, increasing the expression of TNF‐alpha, IL‐1beta, and IFN‐gamma genes [ 154 ]. In ovarian cancer, Shahzad and colleagues demonstrated that LA therapy enhances autophagolysosomes, induces G1 halt in cell‐division cycle progression, elevates miR184 and miR215 expression, and inhibits invasion and migration [ 155 ]. These findings highlight the complex nature of LA's effects on adenocarcinoma cells, showing both pro‐ and anticancer properties depending on the cancer type and experimental conditions [ 158 ]. The diverse effects of LA underscore the need for further research to fully understand its role in cancer biology and its potential as a therapeutic agent or target in cancer treatment. Future studies should focus on elucidating the mechanisms behind these varied effects and exploring how LA's impact on cancer cells might be modulated for therapeutic benefit.

Palmitic Acid

Palmitic acid, a long‐chain saturated fatty acid found abundantly in plant sources such as cereal grains, maize, and palm fruit [ 159 ], has shown potential anticancer effects across various cancer types. In breast cancer, it causes MCF‐7 cells to undergo apoptosis by downregulating Bcl‐2 and upregulating p53, Bax, and caspases [ 160 ]. For colorectal cancer, palmitic acid (10–480 μM) inhibits cell survival and mobility in multiple cell lines through various pathways, including decreased STAT3 and NF‐κB expression and increased CD68 expression [ 161 ]. Palmitic acid (10–25 μM) prevents PC3 cells from migrating and invading prostate cancer by downregulating exosomes and caveolin 1 [ 162 ]. For myeloma, palmitic acid (50–1000 μM) decreases cell survival and increases apoptosis in U266 and RPMI‐8226 cells [ 163 ]. These findings suggest that Inhibiting cell growth and encouraging apoptosis are the main ways palmitic acid may have wide anticancer capabilities; nevertheless, further studies are required to completely comprehend its processes and therapeutic uses.

Stearic Acid

Stearic acid is a saturated fatty acid that may be found in a variety of foods in quite high amounts and has been researched for its potential cancer‐fighting properties [ 164 ]. Stearic acid demonstrates multiple beneficial effects in breast cancer (Hs578t, MDA metastasis breast carcinoma cell 231, Hs578Bst, MCF‐10A, and MDA‐MB‐435 cell lines). In a dose‐dependent manner, it increases the synthesis of DAG and PKC, suppresses cell invasion and migration, and induces apoptosis through increased caspase‐3 activity and PARP cleavage [ 165 ]. Furthermore, epidemiological data indicate that dietary stearic acid consumption is negatively related to postmenopausal women's risk of breast cancer. The anticancer properties of stearic acid extend to other cancer types as well. Stearic acid has been indicated to reduce PDK1 and bcl2 and activate caspase in a dose‐dependent fashion in colon cancer cell lines (DLD‐1, HCT 116, Caco‐2, and NIH‐3T3), ultimately leading to programmed cell death [ 166 ]. In addition, R. P. Gleeson et al.and colleagues found that stearic acid suppresses HOG‐1 cell growth (in vitro) in a dose‐dependent way [ 167 ]. Although these results point to the potential of stearic acid as a therapeutic agent or dietary component in cancer prevention and therapy, more investigation is required to completely comprehend its processes and its clinical uses.

Oleic Acid (OA)

Mono‐unsaturated omega‐9 fatty acid known as OA is present in a variety of plant and animal sources and has demonstrated anticancer properties across multiple cancer types. OA decreases cell growth in breast adenocarcinoma cells (SK‐Br3 and BT‐474) by suppressing p185Her‐2/neu expression, decreasing the activity of AKT and MAPK signaling pathways, and causing caspase‐3‐dependent PARP cleavage to trigger apoptosis [ 168 ]. In esophageal cancer (OE19 and OE33 cell lines), OA dose‐dependently upregulates the level of expression of tumor suppressor genes (p53, p21, and p27) [ 169 ]. In Hep3B and Huh7.5 liver adenocarcinoma cells, OA induces apoptosis and senescence by increasing PARP cleavage and caspase‐3, downregulating c‐Flip and Bcl‐2, and inhibiting the expression of PCNA and cyclin‐D1 to prevent cell viability, proliferation, invasion, and migration [ 25 ]. In A549, HuH‐7, MCF‐7, DLD‐1, and LoVo, various lung cancer cell lines, OA (30 and 50 μM), induce apoptosis by upregulating caspase‐3 and Bax and decreasing the PD‐L1, Bcl‐2, and p‐STAT1 levels [26]. Oleic acid can be a therapeutic agent by modifying important signaling pathways in various cancer types, but further study is required to fully comprehend this potential and develop practical applications.

Miscellaneous

Alpha‐Terthienyl Methanol

Alpha‐terthienyl methanol, a naturally occurring terthiophene identified in various plants, has exhibited promising anticancer properties in different types of cancer. In breast adenocarcinoma cells, alpha‐terthienyl methanol has been observed to enhance apoptosis and trigger the production of ROS [ 178 ]. In the case of cervical cancer, the compound (50 µM) displayed cytotoxic effects by promoting HeLa cell death [ 117 ]. Particularly noteworthy are the significant impacts of alpha‐terthienyl methanol (2–2 µM) on multiple ovarian cancer cell lines, such as A2780, SKOV3, OVCAR3, and ES2, as reported by U. H. Preya and co‐authors. Its actions include inhibiting proliferation, inducing apoptosis through various routes like CDK A/D2 downregulation, ROS production increase, a halt in cell‐division cycle progression at G1 and G2/M phases, and p53 upregulation [ 184 ]. These diverse mechanisms, encompassing apoptosis induction, proliferation inhibition, cell cycle progression modulation, and oxidative stress increase, underscore the potential of alpha‐terthienyl methanol as an anticancer agent. Nonetheless, it is crucial to acknowledge that the research on this compound remains limited, necessitating further investigations to comprehensively elucidate its anticancer potential and potential clinical applications.

Chemotherapeutic Activities of Phytochemical From Eclipta prostrata at Preclinical Models/In Vivo Models

Preclinical chemotherapeutics study of active phytochemicals from E. prostrata involves evaluating the plant's bioactive compounds for their anticancer potential on animal models to assess their efficacy in tumor progression. The study typically involves administering these compounds to the models, monitoring tumor progression, and analyzing biochemical markers to understand the mechanisms of action. This study could contribute to developing natural, plant‐based cancer therapies.

PCA (500–2000 ppm) halts the development of oral carcinogenesis by regulating cell growth in the F344 rat model [ 101 ]. It was also documented that this compound hindered tumorigenesis and inflammation in the esophagus by reducing biomarker (COX‐2, iNOS, p‐NF‐kB, and sEH) and cytokine (PTX3) expression in F344 rats [ 110 ]. Another in vivo analysis conducted by G. D. Stoner and N. P. Seeram revealed that alpha‐amyrin amplifies the apoptotic process in DU‐145 prostate cells, accompanied by the release of cytochrome c, activation of caspases, and downregulation of c‐IAPs, which are implicated in regulating the p53 gene and inducing tumor suppression by inhibiting cyclin‐dependent kinases (CDKs) [ 124 ]. The administration of palmitic acid (50 mg/kg) in mouse xenograft gastric cancer models impeded cell growth, suppressed invasion, and induced apoptosis by reducing the activity of p‐STAT3 and p‐JAK2 and the expression of N‐cadherin and vimentin [ 133 ]. In mouse melanoma B16‐F0 and B16‐F10 cells, beta‐amyrin (58 µM) demonstrated potential for reducing proliferation with cytotoxic effects [ 139 ]. R. Raina and colleagues reported that luteolin treatment augmented the expression of proapoptotic genes, such as APAF1, BAX, BAD, BID, BOK, BAK1, TRADD, FADD, FAS, and Caspases 3 and 9, while diminishing the expression of antiapoptotic genes, such as NAIP, MCL‐1, and BCL‐2. Subsequent to treatment, cell cycle regulating genes like CCND1, 2, and 3, CCNE2, CDKN1A, CDKN2B, CDK4, and CDK2 were downregulated [ 198 ]. According to Liu and colleagues, in vitro and in vivo investigations revealed that luteolin suppressed ovarian cancer cell growth and migration by reducing MMP2 and MMP9 expression levels [ 156 ]. In in vivo trials with Balb/C animals in breast cancer, stigmasterol significantly decreased cell viability, induced apoptosis, and reduced tumors by lowering BCL‐XL and Bcl‐2 levels [ 157 ]. An in vivo exploration of stigmasterol (200–400 mg/kg) induced DNA damage and altered liver enzyme levels while elevating glutathione, superoxide dismutase, and catalase levels in Swiss albino mice [ 170 ]. Mice xenograft models treated with 50–100 µM doses of UA exhibited inhibitory effects on cell migration, promoted apoptosis, and reduced cell growth by influencing molecular targets, including signaling pathways associated with cancer development, RASSF1, MST1, MST2, LATS1, YAP1, FOXM1, KRAS, BATF, and CTGF [ 199 ]. In a female athymic nude mouse model of prostate cancer, UA decreased cell growth, induced apoptosis, and modulated Bcl‐2, Bcl‐xL, Survivin, caspase‐3, PI3K, phosphorylation of Akt, and mTOR signaling in a dose‐dependent manner [ 115 ]. Furthermore, in Balb/c nude (Nu/Nu) mice, wedelolactone triggered apoptosis, inhibited cell migration and invasion by downregulating c‐Myc mRNA and the expression of survivin, cyclin D1, Aurora kinase, TMPRSS2, ADAMTS1, PCNA, and Gemin4 and upregulating ATF3 in a dose–response fashion [ 200 ]. Oleanolic acid affected the male BALB/c athymic (nude) mice colorectal cancer model by reducing angiogenesis and cell growth, thereby decreasing the expression of VEGF A, bFGF, and STAT3 as well as SHH signaling pathways [ 201 ]. The same animal model and compounds were employed in cervical cancer research, revealing that oleanolic acid hindered tumor progression, cell growth, and cell survival by upregulating TfR1 and ACSL4 and downregulating FTH1 ROS and iron (Fe2+) levels [ 202 ]. Oleanolic acid induced apoptosis, halted cell‐division cycle progression, and diminished cell survival and proliferation in prostate cancer cell lines PC‐3, DU145, and LNCaP cells both in vitro and in vivo in a manner dependent on dosage. It impacted various molecular targets, such as CDK4, cyclin D1, MMP, ROS, LMP, caspases, Bcl‐2 family proteins, PI3K, AKT, and GSK‐3 [ 125 ]. This compound also boosted apoptosis, decreased cell viability, and modified the expression of cleaved PARP, Bax, Bcl‐2, and multiple signaling markers related to the NF‐κB pathway in skin cancer A375SM and A375P cells in vitro and in vivo at different doses [ 126 ]. Additionally, oleic acid exhibited promising anticancer properties in preclinical models. In nude mice, oleic acid controlled cell growth and apoptosis by inhibiting the phosphorylation of Akt, mTOR, S6K, 4E‐BP1, and ERK1/2 while increasing cleaved caspase‐3 and p53 levels and decreasing Bcl‐2 expression [ 203 ]. These results underscore the extensive anticancer capabilities of these phytochemicals in various cancer types, mainly by inducing apoptosis, hindering cell growth, and regulating crucial signaling pathways. Further investigation, including clinical trials, is essential to comprehensively grasp their mechanisms and potential applications in cancer treatment.

Synergistic Effects of Phytochemicals in Combination With Conventional Drugs Against Cancer

The principle of synergy, where combined substances produce a greater impact than their individual actions, plays a vital role in the treatment of cancer due to its potential to improve effectiveness and decrease adverse reactions. Cynaroside has exhibited promise in mitigating the side effects of traditional chemotherapy medications like cisplatin by reducing cisplatin‐induced nephrotoxicity and apoptosis in kidney cells [ 78 ]. When wedelolactone is combined with cisplatin in ovarian cancer, it significantly boosts cytotoxicity by suppressing NF‐κB expression and lowering drug resistance markers, such as ETS1 and P‐gp, thereby sensitizing PA‐1 cells to cisplatin [ 204 ]. Furthermore, in cervical cancer, it demonstrates synergistic effects with cisplatin, irrespective of the administration sequence, leading to increased cellular accumulation of platinum and targeting crucial resistance factors like Chk1 and Nrf2 [ 205 ]. Research has revealed its ability to downregulate c‐Myc in prostate tumor cells, synergizing with enzalutamide to decrease cell survival and invasion [ 200 ]. Similarly, a study conducted by E. S. İstifli and collaborators indicated that α‐linolenic acid, when combined with cisplatin, can elevate the levels of antiapoptotic protein bcl‐2. Examination at a histopathological level demonstrated that the combined effect of α‐linolenic acid reduced cisplatin‐induced kidney damage, showcasing its protective anti‐inflammatory and antioxidative properties against nephrotoxicity in mice [ 206 ]. Studies have highlighted that apigenin sensitizes HeLa cells to paclitaxel‐induced apoptosis by inhibiting superoxide dismutase (SOD) activity and fostering the accumulation of reactive oxygen species (ROS) [ 207 ]. Its role as a chemosensitizer is further corroborated by its capacity to enhance the impacts of sorafenib and diminish sorafenib‐induced toxicity in Swiss albino mice [ 208 ]. Chen and colleagues reported that in NSCLC, diosmetin enhanced the antitumor efficacy of paclitaxel by inducing selective apoptosis through ROS accumulation and disrupting the PI3K/Akt/GSK‐3β/Nrf2 pathway without causing notable toxicity to normal cells [ 69 ]. Z. Li and colleagues illustrated that protocatechuic acid (PCA) combined with 5‐fluorouracil (5‐FU) and oxaliplatin (OXA) enhances the efficacy of colon cancer treatment while possibly decreasing side effects. At a concentration of 50 µM, PCA significantly inhibited cell survival and increased cytotoxicity and apoptosis in Caco‐2 cells. The combination, particularly at a 2:1 ratio of 5‐FU to PCA, exhibited maximal synergistic effects and enhanced antitumor activity by regulating MMP‐2 and MMP‐9 expression in a dose‐ and time‐dependent manner [ 209 ]. Moreover, a novel PCA‐based hydrogel combined with isoguanosine (isoG) demonstrates potent anticancer properties by activating the JNK/P38 pathway and targeting SerpinB9 (Sb9), effectively restraining cancer growth [ 210 ]. In the context of breast cancer, ascorbic acid triggers hydrogen peroxide production in tumor cells, significantly intensifying topotecan cytotoxicity in MCF‐7 breast tumor cells by enhancing topotecan‐induced DNA cleavage and double‐strand breaks, resulting in topoisomerase I‐dependent DNA damage and necrosis [ 211 ]. Similarly, the combined action of ascorbic acid and retinoic acid in hindering MCF‐7 human breast carcinoma cell growth may involve gene expression for differentiation and upregulation of antioxidant enzymes and proteins implicated in apoptosis, cell cycle regulation, and DNA repair [ 212 ]. Moreover, ascorbic acid and the glycolysis inhibitor 3‐PO cooperate to prompt apoptosis in NSCLC cells through a ROS‐dependent mechanism, leading to a significant increase in cell death in comparison to individual drug treatments [ 46 ]. Chen et al. discovered that the combined effect of luteolin (LUT) and oxaliplatin (OXA) reduced the growth of gastric adenocarcinoma cells (SGC‐7901) and initiated apoptosis by modulating the cell cycle and activating the Cyt c/caspase signaling pathway [ 189 ]. Furthermore, LUT, in conjunction with asiatic acid (AsA) induced apoptosis and caused sub‐G1‐phase arrest in cervical carcinoma cells (CaSki and HeLa) by regulating various signaling pathways, such as PI3K/AKT, JNK/p38 MAPK, and FAK, while upregulating ERK signaling [ 213 ]. Another research conducted by Mitchel et al. concluded that the combination of luteolin and quercetin with 5‐FU decreased proliferation and induced apoptosis in colon cancer cells (HT‐29) by enhancing the expression of specific genes like p53, Bax, p38 MAPK, and PTEN [ 214 ]. Consistent with this, the combination of stearic acid with 5‐Fluorouracil was found to significantly enhance the efficacy of 5‐FU in eliminating cancer cells by promoting programmed cell death and reducing the expression of the cell survival protein Bcl‐2 in colorectal adenocarcinoma (DLD‐1) cells [ 166 ]. In a study by Cao and colleagues, it was reported that β‐sitosterol, a phytosterol, in combination with gemcitabine, resulted in increased G0/G1 halt in cell‐division cycle progression, decreased NF‐κB activity, upregulated Bax protein, and downregulated Bcl‐2 protein, suggesting a more effective induction of apoptosis in pancreatic cancer cell lines (PC, MIAPaCa‐2, and BXPC‐3) [ 215 ]. Kato and colleagues highlighted that oleic acid downregulated the expression of the receptor tyrosine kinase ErbB2 and enhanced the effects of vinblastine in breast adenocarcinoma cells (MCF‐7 and SK‐BR‐3) [ 216 ]. Gautam and colleagues investigated that stigmasterol, a phytosterol, augmented the anticancer properties of doxorubicin in triple‐negative breast tumor cells (MDA metastasis breast carcinoma cell 231 and MCF‐7) by increasing CD44 protein expression [ 217 ]. Wang and colleagues demonstrated that the combined treatment of 4‐hydroxybenzoic acid and doxorubicin synergistically increased apoptosis in MCF‐7 estrogen receptor‐positive cells through the upregulation of the HIPK2/p53 pathway, enhanced caspase‐3 and PARP cleavage, G2/M halt in cell‐division cycle progression induction, and downregulation of HDAC6 [ 34 ]. Additionally, Avcı and colleagues assessed that the combination of oleanolic acid and maslinic acid exhibited synergistic effects with doxorubicin in the MCF‐7 breast tumor cell line, resulting in increased G0/G1 halt in cell‐division cycle progression and inhibition of the PI3K/AKT/mTOR signaling pathway [ 218 ]. In colorectal cancer, Shan and colleagues demonstrated that ursolic acid enhanced the anticancer activity of oxaliplatin by reducing the expression of antiapoptotic proteins (Bcl‐xL, Bcl‐2, and survivin), activating caspases‐3, 8, and 9, and inhibiting various signaling pathways [ 219 ]. Finally, a study by Qining et al. indicated that palmitic acid and epalrestat downregulated AKR1B10 expression, reduced matrix metalloproteinase (MMP) activity, and increased reactive oxygen species (ROS) production in the cholangiocarcinoma cell line RBE [ 220 ]. These studies collectively present compelling evidence that combined treatments of bioactive compounds with chemotherapeutic agents hold significant promise in enhancing anticancer efficacy while minimizing side effects in a variety of cancer types through the modulation of crucial cellular pathways and gene expressions involved in apoptosis and drug resistance. The summary of synergistic effects against cancer is tabulated in Table 2 .

Role of Phytochemical‐Based Nanoformulation in Treating Human Malignancies

Phytochemical‐based nanoformulations have become a promising strategy in cancer treatment, as they enhance the bioavailability, solubility, and targeted delivery of therapeutic agents, effectively overcoming the limitations of conventional chemotherapy. Thi‐Kim‐Chi Huynh et al. reported that a phytosome‐based nanoformulation of diosmetin (Dt‐Ph) has four times higher solubility in buffered media compared to diosmetin alone, indicating its greater hydrophilicity. Additionally, cytotoxicity tests on HEK‐293A cells revealed that Dt‐Ph is less harmful to normal cells than diosmetin [ 222 ]. In breast cancer therapy, encapsulating wedelolactone in PLGA nanoparticles boosts drug retention and uptake in cancer stem cells (CSCs). This augmentation enhances paclitaxel's effectiveness by reducing the expression of SOX2 and ABCG2, which are pivotal in conferring drug resistance [ 223 ]. The nanoparticle loaded with apigenin and conjugated with an aptamer demonstrated improved pharmacokinetics and biodistribution, resulting in increased colon retention compared to both the unbound drug and the nanoparticle without an aptamer. This led to enhanced therapeutic effectiveness against colorectal cancer cells while minimizing nonspecific toxicity to healthy cells [ 224 ]. A study conducted by M. K. Pal and colleagues revealed that the combination of graphene oxide‐coated nanotized apigenin with paclitaxel (GO‐NA/PTX) synergistically enhanced the antiproliferative effects when compared to individual treatments of GO‐NA and PTX. This synergistic effect was accompanied by a significant reduction in SOD activity, elevation of ROS levels, disruption of mitochondrial function, DNA damage, halt in cell‐division cycle progression, and, ultimately, induction of apoptosis [ 225 ]. Within the context of non‐small cell lung cancer (NSCLC), Superparamagnetic Iron Oxide Nanoparticles carrying PTX and coated with trans‐10, cis‐12 conjugated linoleic acid (CLA) demonstrated efficient drug delivery with minimal adverse effects [ 226 ]. An important investigation by K. Buskaran and colleagues illustrated that functionalized graphene oxide‐loaded PCA nanocomposites displayed notable anticancer properties in liver carcinoma cells (HepG2), leading to late‐stage apoptosis, a halt in cell‐division cycle progression, mitochondrial dysfunction, and an increase in reactive oxygen species. These nanocomposites exhibited higher efficacy and lower toxicity in comparison to unmodified protocatechuic acid and nanocomposites without folic acid coating [ 227 ]. Moreover, another study showcased that a nanocomposite formulation containing protocatechuic acid and coated with folic acid effectively targeted overexpressed folate receptors in colorectal (HT29) and liver (HepG2) tumor cells, resulting in enhanced anticancer effects and sustained release of the drug [ 228 ]. In breast adenocarcinoma cells, PEGylated chitosan nanoparticles with ascorbic acid have significantly reduced systemic toxicity, enhanced absorption and stability, and demonstrated apoptotic actions [ 229 ]. When treating aggressive tumors such as pancreatic cancer, combining ascorbic acid with other therapeutic agents can improve the effectiveness of drug delivery. In vitro, experiments on human pancreatic ductal adenocarcinoma cells exhibited apoptosis‐mediated cytotoxicity and the best cytotoxic effect. Similarly, In vivo experiments conducted on mice models harboring PANC‐1‐induced tumors showed that the complex notably decreased tumor volume [ 230 ]. In leukemia cancer, Neto and colleagues found that kollicoat Mae 100 P‐coated nanocapsules encapsulating α‐amyrin selectively caused cytotoxicity and apoptosis in human leukemia cells (Kasumi‐1), demonstrating potential as a therapeutic approach for acute myeloid leukemia [ 231 ]. Oral administration of luteolin is limited because of its poor solubility. Biodegradable proteins like zein and sodium caseinate are used as nanocarriers to address this, improving encapsulation efficiency and targeted release at intestinal pH [ 232 ]. F. Q. T. Fu and colleagues have demonstrated that luteolin‐loaded zein nanoparticles increase cytotoxicity by causing apoptosis in SW480 colon cancer cells. Additionally, nanoparticles made with ROS‐responsive materials, such as PPS‐PEG, have improved anti‐melanoma effects both in vitro and in vivo [ 233 ]. Additionally, luteolin in combination with polylactic acid and polyethylene glycol with a methoxy end group (PLA‐PEG‐Ome) nanoparticles reduced the size, growth, and colony formation of tumors in animals bearing squamous cell carcinoma Tu212 cells, lung carcinoma cells, as well as head and neck tumors in xenograft mouse models [ 234 ]. Redox‐responsive chitosan/stearic acid nanoparticles (CSSA NPs) were created by A. Sood and associated with the purpose of delivering two drugs at once to cure cancer. These 200 nm nanoparticles effectively encapsulate curcumin and doxorubicin by using disulfide crosslinking, improving therapeutic effectiveness [ 235 ]. Additionally, PEGylated stearic acid‐grafted chitosan micelles functionalized with A54 peptide show promising internalization and distribution into liver carcinoma cells, indicating the potential for reduced toxicity treatment [ 236 , 237 ]. Afzal and colleagues investigation into the synthesis and characterization of β‐sitosterol‐encapsulated alginate and chitosan nanoparticles revealed the possibility of its use as a breast cancer treatment [ 238 ]. In melanoma, glioblastoma, and breast cancer, Parveen et al. used oleic acid to produce temperature‐activated nanoparticles (TANs), which showed improved efficacy in delivering the chemotherapy medication doxorubicin when compared to the drug's unbound form [ 221 ]. Another study by Z. Torres and colleagues showed that oxidative stress and caspase‐3/7 activation caused by stigmasterol‐loaded solid lipid nanoparticles (Stg‐SLNs) enhanced apoptosis [ 239 ]. Solid lipid nanoparticles combined with oleanolic acid and green iron oxide nanoparticles had strong cytotoxic effects on lung tumor cells (A549), as shown by C. Prodan‐Băsesc et al. [ 100 ]. Furthermore, ursolic acid and folic acid (FA) were added to the pH‐sensitive chitosan (CS) and mesoporous silica nanoparticles (MSNs), which significantly reduced the growth, invasion, and migration of carcinoma cells [ 173 ]. Kalaycioglu and colleagues synthesized biocompatible nanostructured lipid carriers (NLCs) of palmitic acid, increasing lipophilicity and controlled release capacity [ 240 ]. The summary of nano‐based efficacies with chemotherapeutic activities of active compounds is displayed and tabulated in Figure 3 and Table 3 .

Pharmacokinetics Activity and Challenges of Active Compounds Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME/TOX)

properties—absorption, distribution, metabolism, excretion, and toxicity—are crucial factors in the development of new drugs. Pharmacokinetics properties were carried out in silico using computational tools, including Schrodinger's QuickPro modules, admetSAR, and SwissADME [ 241 ]. Among the compounds analyzed, 25 identified compounds follow the “rule of five”, demonstrating favorable molecular properties (Figures 4 and S2 ). Only one compound violated two criteria, and eight broke a single criterion. Lipinski's Rule of five (Ro5) defines orally available drugs within specific ranges: molecular weight (130.0–725.0), octanol to water partition coefficient (−2.0 to 6.5), number of hydrogen bond donors (0.0–6.0), and hydrogen bond acceptors (2.0–20.0). Our analysis revealed promising results within these parameters. All the compounds had molecular weights between 140 and 460 Daltons. Although five compounds exhibited less than ideal octanol/water partition coefficients, most were highly water soluble. Additionally, the number of hydrogen bond donors mostly fell within the range of 1–6, with one exception having fewer than one, while hydrogen bond acceptors ranged from 2 to 13, except for one compound that had fewer than two. Most compounds have more significant results, positioning them as promising drug candidates.

However, translating these favorable in silico predictions and promising preclinical findings into clinically viable phytopharmaceuticals faces considerable hurdles. Beyond the scientific complexities, the development of phytopharmaceuticals faces distinct regulatory challenges. Unlike synthetic drugs, the diverse chemical composition and natural variability of plant‐derived compounds necessitate robust standardization protocols for extract purity, potency, and consistency. Regulatory bodies often require comprehensive data on batch‐to‐batch reproducibility, detailed analytical characterization, and evidence of a well‐defined mechanism of action, which can be particularly intricate for multi‐component herbal formulations. Establishing clear regulatory pathways for approval, including streamlined processes for traditional medicine‐derived agents while ensuring rigorous safety and efficacy standards, remains a significant hurdle in bringing these promising natural compounds from bench to bedside.

Limitation of the Study and Future Recommendations

It is our good luck that the compounds from E. prostrata are effective against cancer. However, according to our literature, we found some limitations. Most studies on E. prostrata are conducted in vitro, and some are in the preclinical phase. Hence, clinical trials on human subjects are lacking to validate these findings. Thus, phase I, II, and III clinical trials have to be carried out to assess E. prostrata's effectiveness in cancer patients. Variability in the composition of plant extracts can lead to inconsistent results. After identification by High‐Performance Liquid Chromatography (HPLC) or other standardized methods from E. prostrata , each phytochemical needs to be synthesized and tested to test their efficacies for chemotherapeutic activities. While some studies suggest anticancer properties, the precise molecular mechanisms by which E. prostrata exerts its effects are not fully understood. Here, we just predicted in silico pharmacokinetics study. However, the absorption, distribution, metabolism, and excretion (ADME) of E. prostrata phytochemicals in the human body are not well‐characterized. This limits the ability to predict their efficacy and safety in humans. Although the phytochemicals from E. prostrata showed some synergistic activity, more research is required to determine whether E. prostrata may be utilized in conjunction with other therapies like radiation and chemotherapy.

While our findings robustly highlight the significant potential of E. prostrata phytochemicals as anticancer agents, the inherent challenges in establishing their definitive efficacy and safety in complex biological systems warrant rigorous further investigation. This includes overcoming issues, such as standardized dosing, potential drug interactions, and the critical need for comprehensive toxicological profiles and large‐scale human trials. One of the most notable limitations of these compounds is their bioavailability. Using bioinformatics tools, we determined that only a few compounds exhibited low bioavailability scores (Figure 5 ). Nevertheless, we have already addressed a potential solution by proposing nano‐formulation approaches, which can enhance the solubility and thereby improve the overall bioavailability of these compounds. Furthermore, for future clinical translation, it is imperative to thoroughly investigate potential herb‐drug interactions, especially when considering the synergistic application of E. prostrata phytochemicals with conventional chemotherapeutic agents. Such interactions, which could arise from shared metabolic pathways (e.g., cytochrome P450 enzymes) or additive/antagonistic pharmacological effects, necessitate comprehensive in vitro and in vivo studies to ensure efficacy and patient safety and to establish appropriate dosing regimens for combination therapies. Moreover, a deeper understanding of their precise multi‐target interactions and synergistic effects in varied tumor microenvironments will be crucial for optimized therapeutic strategies.

Conclusion

The complexity of cancer necessitates a multifaceted approach to treatment. Including phytochemicals in current treatment plans has the potential to enhance patient outcomes. By utilizing nature's resources, scientists can create new, potent anticancer treatments that target important cancer hallmarks while minimizing side effects. The present review investigates that the phytochemicals obtained from E. prostrata are a valuable resource for the creation of novel therapeutic interventions for cancer. Our investigation uncovers a wide range of molecules with promising antitumor activity against multiple cancer types and employs distinct action mechanisms. Compounds from this plant showed promise in inducing apoptosis, preventing cell division, and disrupting vital signaling pathways linked to the advancement of cancer (Figure 6 ). According to the literature review, ursolic acid, oleanolic acid, beta‐sitosterol, 3,4‐dihydroxybenzoic acid, and diosmetin (Supporting Information) might be the most promising phytochemicals for clinical development. Additionally, apigenin, cynaroside, wedelolactone, and ascorbic acid are among the phytochemicals that have demonstrated synergistic interactions with traditional chemotherapeutic drugs, indicating the possibility of increased therapeutic efficacy and decreased toxicity. The development of sophisticated drug delivery technologies and the integration of phytochemicals with traditional therapies show promise for improving therapeutic efficacy and minimizing side effects. Even though there is encouraging evidence that these phytochemicals have anticancer effects, more research is necessary. To clarify the exact molecular targets and signaling pathways implicated in their anticancer actions, comprehensive mechanistic studies are necessary. By addressing the limitations of current research and conducting rigorous clinical trials, we can unlock the full potential of E. prostrata ‐derived phytochemicals in the fight against cancer.

Author Contributions

Md. Sakhawat Hossain: writing – original draft, writing – review and editing. Sanjida Khatun: writing – original draft. Md Mojnu Mia: writing – original draft. Fatematuz Zohora: writing – original draft. Md. Rifat Sarker: writing – original draft. K. M. Tanjida Islam: writing – original draft. Md. Abu Sayeed: writing – original draft. Moushumi Afroza Mou: writing – original draft. Sherif Hamidu: writing – review and editing. Fatima Hamidu: writing – original draft. A. M. Wasaf Hasan: writing – original draft. Sanjida Mumtaj: writing – original draft. Md Khaled Hossain: writing – original draft. Md Sohel: writing – original draft, writing – review and editing, conceptualization, supervision.

Funding

The authors received no specific funding for this study.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supplementary‐file‐S1.

Acknowledgments

This study did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. The authors confirm that no paper mill and artificial intelligence was used.

Hossain M. S., Khatun S., Mia M. M., et al., “Screening the Active Phytochemicals From Eclipta prostrata and Unraveling Their Molecular Insight Into Human Malignancies,” Cancer Innovation 4 (2025): 1‐41. 10.1002/cai2.70038.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

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Associated Data

Supplementary Materials

Supplementary‐file‐S1.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.