Curcuma longa, commonly known as turmeric, is a staple spice in Indian and Southeast Asian cuisine, is one of the most studied medicinal herbs for its anticancer properties (Verma et al., 2018). Its primary bioactive constituent, curcumin, has garnered substantial attention for its broad-spectrum antineoplastic effects across various cancer types. Curcumin exerts its anticancer activity through modulation of multiple molecular targets and signaling pathways (Kunnumakkara et al., 2017a). It inhibits cell proliferation by downregulating cyclins and cyclin-dependent kinases, induces apoptosis via activation of caspases (Srivastava et al., 2007) and mitochondrial pathways (Das and Vinayak, 2014), suppresses angiogenesis (Saberi-Karimian et al., 2019) by downregulating vascular endothelial growth factor (VEGF) expression, and interferes with metastatic progression by modulating matrix metalloproteinases (MMPs). Additionally, it also modulates key signaling pathways implicated in cancer pathogenesis, including NF-κB, STAT3, and PI3K/Akt, thereby disrupting the cancer cell’s survival and proliferation, and inflammatory signals (Shishodia et al., 2005).

One of the advantages of curcumin is its low toxicity profile, even at relatively high doses, making it a safe candidate for long-term adjunctive therapy. Curcumin has demonstrated preclinical and clinical efficacy against a variety of malignancies, including breast, colon, prostate, lung, and pancreatic cancers (Aggarwal et al., 2003). Moreover, it enhances the efficacy of conventional chemotherapy and radiotherapy while alleviating associated side effects, such as mucositis, oxidative stress, and systemic inflammation.

However, despite these promising therapeutic attributes, cur cumin’s clinical application is limited by its poor bioavailability, attributed to low absorption, rapid hepatic metabolism, and systemic elimination (Anand et al., 2007). To overcome these limitations, several strategies have been developed, including nanoparticle encapsulation, liposomal formulations, structural analogs and co-administration with other herbs such as piperine (Ma et al., 2019).

Withania somnifera, commonly known as Ashwagandha, widely recognized for its rejuvenating, adaptogenic and immunomodulatory properties. Its principal bioactive constituents, Withanolides and Withaferin A, have demonstrated notable anticancer effects in various preclinical studies (Rai et al., 2016). Withaferin A exerts its anticancer activity primarily by inducing apoptosis in malignant cells. It modulates several signaling pathways, including inhibition of NF-κB, activation of tumor suppressor p53, and interference with the cytoskeletal architecture, which disrupts cancer cell integrity and function (Dutta et al., 2019).

Ashwagandha has exhibited cytotoxic effects against a broad range of cancer cell lines, including breast, colon, lung, and prostate cancers (Singh et al., 2021). Furthermore, studies suggest that Withaferin A may enhance the efficacy of standard chemotherapeutic agents by sensitizing tumor cells to apoptosis, thereby offering potential for synergistic cancer therapy and its adaptogenic nature also supports cancer patients by alleviating fatigue, anxiety, and stress, contributing to improved quality of life.

Despite its promising pharmacological profile, clinical data in humans remain limited. Only a few randomized controlled trials have been conducted, making it difficult to conclusively establish safety and optimal dosing for cancer patients. Side effects by its use include gastrointestinal disturbances, drowsiness, and rare allergic reactions (Tandon and Yadav, 2020). Additionally, Ashwagandha may interact with immunosuppressive agents and thyroid hormone medications, warranting caution in patients on such therapies (Bhaskar et al., 2022).

Phyllanthus emblica, commonly known as Indian Gooseberry or Amla, is a cornerstone of Ayurvedic medicine recognized for its potent antioxidant and rejuvenating properties. Its anticancer potential is primarily attributed to its diverse bioactive constituents, including gallic acid, ellagic acid, and emblicanin A and B. These phytochemicals exert anti carcinogenic effects via multiple mechanisms as they induce apoptosis, inhibit tumor cell proliferation, and modulate oxidative stress (Zhao et al., 2015), thereby disrupting the cellular environment that favors malignant transformation. Phyllanthus emblica modulates transcription factors such as NF-κB and AP-1, which play key roles in inflammation-mediated cancer progression (Naseer et al., 2022).

Amla’s greatest strengths lie in its rich antioxidant profile, which not only combats oxidative damage (Gul et al., 2022), a known contributor to carcinogenesis, but also supports general cellular health. Preclinical studies have demonstrated its ability to inhibit the proliferation of cancer cells from breast, cervical, and ovarian malignancies, and it has also shown promise in enhancing immune surveillance by stimulating cytotoxic T cells and natural killer cell activity.

However, despite promising results from in vitro and in vivo studies, clinical validation in human cancer patients is still limited. Most evidence remains preclinical, underscoring the need for well-designed human studies to confirm therapeutic efficacy and establish standardized dosages. In higher doses, Amla may lead to gastrointestinal disturbances such as bloating or diarrhea. It may also interact with anticoagulant medications due to its blood-thinning potential, thus warranting caution in individuals on such therapies (Abebe, 2019).

Piper nigrum, commonly known as Black Pepper, is a culinary spice that also holds significant therapeutic potential due to its bioactive alkaloid, piperine (Srinivasan, 2009). This has been extensively studied for its pharmacological benefits, and has demonstrated notable anticancer activity through multiple molecular mechanisms. It induces apoptosis and inhibits tumor cell proliferation by modulating key molecular targets involved in oncogenesis, including NF-κB, PI3K/Akt, and MAPK signaling pathways. Piperine plays a critical role in enhancing the bioavailability of other anticancer compounds such as curcumin, by inhibiting hepatic and intestinal glucuronidation processes (Ashokkumar et al., 2021). This bioenhancement capacity makes it an attractive candidate for combination therapy in integrative oncology.

One of the most compelling advantages of piperine is its capacity to potentiate the efficacy of co-administered chemopreventive agents. Studies have shown that it exhibits cytotoxicity against a range of cancer cell lines, including breast, lung, colon, and prostate cancers. Piperine also has the potential to overcome multidrug resistance (MDR) in cancer cells by downregulating P-glycoprotein and other drug-efflux mechanisms, which are major limitations in conventional chemotherapy (Li et al., 2011). However, the use of piperine at high doses may lead to gastrointestinal irritation and discomfort. Moreover, due to its influence on hepatic enzymes like CYP3A4 and CYP2D6, piperine may interact with drugs metabolized in the liver, potentially altering their pharmacokinetics and increasing the risk of toxicity (Mehmood and Gilani, 2010; Haq et al., 2021).

Curcumin also demonstrates significant action via growth factors like fibroblast growth factor (FGF), hepatocyte growth factor (HGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-b1 (TGF-b1) and vascular endothelial growth factor (VEGF) (Kunnumakkara et al., 2017b; Sahebkar et al., 2016; Jordan et al., 2016) Curcumin treatment is reported to increase HDAC1, HDAC4 and HDAC8, apoptosis, production of ROS and Nrf2 expression, while decrease VEGF, HIF1-a, GSK-3b, Akt, prostate-specific antigen (PSA) level, PSA mRNA expression, HAT activity and cellular proliferation in prostate and bladder cancer (Taverna et al., 2015). Curcumin treatment also downregulated the expression of VEGF and decreased the phosphorylation of AKT, in leukemia and cervical cancer (Mimeault and Batra, 2011).

Curcumin modulates intracellular signal transduction elements such as p21, p27, inhibitor of growth family member 4 (ING4), cyclin D1, cMyc, VEGF, ICAM-1, MMPS, uPA, COX-2, CXCR-4, Bax, Bad, Bak, Noxa, p53, modulator of apoptosis, caspases, etc. resulting in reversal of cancer incidence, progression and relapse (Kasi et al., 2016).

In cellline studies, Curcumin treatment upregulated E-cadherin while downregulated vimentin and MMPs expressions along with reduced metastasis, cell spreading and cell migration in human papillary thyroid carcinoma cells (Zhang L. et al., 2016). Curcumin treatment induced the arrest of G0/G1 cell cycle phase alongside inhibited the regulatory proteins cyclin D1 and CDK-2 (Sha et al., 2016). Besides, it upregulated the expression of p21, p27 and p53 while downregulated Bcl-2 expression. Further, Curcumin treatment is known to activate caspase (Jemal et al., 2010; Banerjee et al., 2023; Kizhakkeveettil et al., 2024) while decreased Akt, MMP2 and MMP9, Bcl2, Bcl-XL and tumor volume in prostate cancer (Mimeault and Batra, 2011).

Curcumin is known to modulate various cellular signaling cascade like the phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR), ERK5/AP-1, TGF-b signaling, Wnt/b-catenin, PAK1/Ras-related C3 botulinum toxin substrate 1, TLR-4/MyD-88, signal transducers and activators of transcription (STAT) 3 pathway, PPARc-C/EBPa pathway, nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, p38MAPK, etc. (Shanmugam et al., 2015).

Curcumin treatment downregulated chemokine receptor 4 expression and supressed Wnt signaling. In addition, curcumin treatment downregulated vimentin and upregulated E-cadherin expression, which leads to inhibition of proliferation and epithelial mesenchymal transition in SW620 human colon cancer cells (Zhang Z. et al., 2016).

Curcumin mediated downregulation of viral oncogenes is attributed to its ability to modulate apoptosis and prevent NFkB and AP1 translocation thereby suppressing the transcription of HPVs (Divya and Pillai, 2006; Prusty and Das, 2005).

Piperine exhibits a unique duality in its abilities, functioning as both a blocking and a suppressing agent in cancer prevention and therapy. The main chemopreventive mechanism of action of piperine include activation of apoptotic signalling cascades, inhibition of cell proliferation, cell cycle arrest, alterations in redox homeostatis, modulation of ER stress and autophagy, inhibition of angiogenesis, induction of detoxification enzymes, and sensitization of tumors to radiotherapy and chemotherapy (Manayi et al., 2018). Piperine is a pro-oxidant agent and can stimulate the formation of reactive oxygen species (ROS) in many types of cancer cells. ROS triggers the depolarization of mitochondrial membrane potential (MMP), leading to release of cytochrome c, activation of caspases (Lai et al., 2012), and induction of apoptosis.

Piperine attenuates the UV-R induced damage in human HaCaT keratinocytes through its influence on the NF-κB and Bax/Bcl2 pathways. It is believed that piperine binds to active site of NF-κB and blocks its nuclear localization. Altered NF-κB activity in turs triggers suppression of apoptotic marker genes (Verma et al., 2017). Its effects have been reported for different cancer types. In lung cancer, piperine induces apoptosis via p53 signaling. In breast cancer, this substance suppresses proliferation and metastasis both in vitro and in vivo3. In melanoma cells, piperine inhibitis NF-κβ, c-Fos, ATF-2 and CREB (Lin et al., 2014). Piperine suppresses the Wnt/β-catenin pathway and has anti-cancer effects on colorectal cancer cells. Piperine inhibits proliferation, causes cell cycle arrest and induces autophagy in prostate cancer cell lines (Lai et al., 2012). In rectal cancer, piperine increases reactive oxygen species leading to apoptosis increase (Pradeep and Kuttan, 2004). Additionally, some effects of piperine on colorectal cancer were reported, such as inhibition of cell proliferation and activation of apoptotic program by endoplasmic reticulum stress (Ouyang et al., 2013). However, piperine molecular mechanisms of action on colorectal cancer have not been elucidated, as well as its relation to the Wnt signaling pathway.

Piperine also blocked the phosphorylation of Ser 473 and Thr 308 residues of Akt involved in regulating endothelial cells and, therefore, angiogenesis (Yaffe et al., 2013). Piperine downregulated MMP-9 and VEGF mRNA expressions in a dose-dependent manner. In addition, piperine treatment increased the expression levels of E-cadherin, a cell adhesion molecule required to maintain extracellular matrix integrity and cell-to-cell contact, thereby supporting the anti-metastatic potential of this alkaloid (Yaffe et al., 2015). Piperine induces various cell death types, including apoptosis, autophagy, ferroptosis, and anoikis, which play significant roles in cancer prevention and therapy (Jafri et al., 2019; Qi et al., 2023; Fofaria and Srivastava, 2015). Piperine can also inhibit the cell cycle at the G2/M phase in cancer cells via the downregulation of G2-associated (cyclin B, CDK1, Cdc25C) proteins, the induction of p21, and the enhancement of the phosphorylation of both CDK1 and checkpoint kinase 2 (Chk2) (Zhang et al., 2015; Greenshields et al., 2015; Pressete et al., 2023). Piperine enhanced the bioavailability of various well-known chemopreventive natural agents (e.g., resveratrol, curcumin), by inhibiting glucuronidation, significantly increasing the plasma concentration of resveratrol when given with resveratrol.

Withania somnifera (Ashwagandha), particularly Withaferin A, exhibits extensive anticancer properties via mitochondrial disruption, reactive oxygen species (ROS) generation, and interference with mitotic spindles, resulting in apoptosis (Widodo et al., 2010; Carmi et al., 2012). It inhibits essential oncogenic pathways, including NF-κB, Sp1, Akt, mTOR, STAT3, and Notch-1, while downregulating angiogenesis and epithelial-mesenchymal transition markers such as VEGF, vimentin, Snail, and Slug (Song et al., 2013). In vivo studies demonstrate a reduction in microvessel formation and tumor regression across various cancers, with liposomal and nanosponge formulations markedly improving efficacy (Garvey et al., 2021; Jendrossek, 2013). Docking studies indicate that garcinol exhibits synergistic effects in inhibiting BCL-2/AKT, demonstrating greater efficacy compared to conventional agents such as venetoclax or melatonin (Olarewaju et al., 2022; Huang et al., 2023). Challenges in solubility and bioavailability remain, highlighting the necessity for additional nanotechnological advancements and clinical validation (Balkrishna et al., 2024a).

WA arrested the cell cycle at the G2/M phase and is correlated with decreasing the levels of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C (Cdc25C) protein levels, leading to inhibition of the Cdck1/CyclinB1 kinase complex (Stan et al., 2008). Another mechanism by which WA ceases the cell cycle is by inhibiting the spindle assembly checkpoint (SAC). SAC is a mitotic checkpoint complex consisting of Mad1 and Mad2 components, which are essential for the initiation of anaphase (Das et al., 2014). In the MDA-MB-231 xenograft model, WA showed an anti-metastatic effect through inhibition of vimentin expression (Lee et al., 2015). WA inhibited vimentin assembly by directly binding to cysteine 328 residues through covalent modification and also inhibited proteasomal activity in a vimentin-dependent manner in the case of breast cancer (Thaiparambil et al., 2011). The matrix metalloproteinase inhibition is observed to be mediated through suppression of the Akt pathway (Lee et al., 2013).

Phyllanthus emblica (amla), which contains high levels of Emblicanin A/B (ellagitannins), demonstrates significant antioxidant and anti-inflammatory properties by inhibiting reactive oxygen species (ROS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase (COX), and inducible nitric oxide synthase (iNOS) (Im et al., 2018; Yang et al., 2018). Recent findings indicate tumor-suppressive potential in hepatotoxic and nephrotoxic models, as well as anti-fibrotic activity through caspase-3-mediated apoptosis (Kim et al., 2024; Hussein et al., 2020).

Flavonoids in E. officinalis such as apigenin and luteolin can inhibit HCC cell proliferation, migration, and invasion by inducing apoptosis via inhibiting the AKT/osteopontin and PI3K/Akt/mTOR pathways, respectively (Im et al., 2018; Yang et al., 2018). Phenolic compounds such as ferulic acid and vanillic acid have antioxidant properties and can target PTGS2 implicated in inflammation and tumor progression thereby inhibiting NF-κB signaling pathway (Kim et al., 2024). Caffeic acid, chlorogenic acid, o-coumaric acid have been reported to exhibit anti-inflammatory and antioxidant properties that contribute to hepatoprotective effects by targeting tyrosine receptor kinases, EGFR and VEGFR, by modulating MAPK and PI3K/AKT pathways, respectively (Hussein et al., 2020; Yang et al., 2021) Likewise, pyrogallol inhibits PI3K/AKT/Skp2/cMYC signaling pathways in HCC (Ahn et al., 2019).

Caspases serve as a primary mediator of apoptosis located in the cytosolic space (van Loo et al., 2002). The treatment of emblicanin-A to PC-3 cells increased the caspase-3 and-9 mRNA expression compared to untreated cells which might the mechanism that emblicanin-A lead to the release of cytochrome c from mitochondrial space which would have been combined with an adaptor molecule apoptosis protease activating factor 1 and also with an inactive initiator caspase, pro-caspase-9 within a multiprotein complex called the apoptosome, causing a series of caspase and that ultimately would have caused apoptosis (Ghobrial et al., 2005). Hence, it clearly demonstrates that emblicanin-A activates apoptosis by the intrinsic pathway. In support of the present investigation, we found that E. officinalis fruit extract treated rats significantly increased the caspase-3 protein expression (Malik et al., 2016).

The insight mechanism combining two bioactive ayurvedic compounds is also well explored especially the curcumin and piperine bioactives. Curcumin and piperine together have positive effect on serum IgE levels with no significant changes on serum IL-10 and IL-12 in healthy young women (Bahrami et al., 2022). Administration of oral curcumin with piperine as an adjuvant symptomatic therapy in COVID-19 treatment substantially reduce morbidity and mortality, and ease the logistical and supply-related burdens on the healthcare system (Pawar et al., 2021). Piperine also potentiates curcumin’s inhibitory effect on tumor progression via enhancing its delivery and therapeutic activity (Yüksel et al., 2023). Curcumin-C3complex^®/Bioperine^® treatment strongly reduces in vitro tumorigenic properties of mesothelioma cells by impairing cellular self-renewal ability, proliferative cell rate and cell migration and delays tumor growth in xenograft mouse model by reducing angiogenesis and increasing apoptosis (Di Meo et al., 2019). Kaur et al. (2018) concluded that curcumin and piperine, either alone or in combination, have the potential to downregulate mTORC1 signaling in the intestinal epithelium with implications for tumorigenesis and inflammation.

In silico assessments of bioactive compounds derived from Curcuma longa, Phyllanthus emblica, Piper nigrum, and Withania somnifera reveal their significant therapeutic potential across multiple cancer types. Curcumin from Curcuma longa displayed high binding affinity with EGFR (−9.1 kcal/mol) and inhibited PI3K/Akt and NF-κB pathways (Kurmi et al., 2025), while a combination of curcumin and demethoxycurcumin showed multi-targeted interactions with VEGFA, TNF, PTGS2, and AKT1, indicating anti-inflammatory and pro-apoptotic activity. Emblicanin B, gallic acid, quercetin, and ellagic acid from Phyllanthus emblica demonstrated effective docking with CASP3 (−8.7 kcal/mol), TP53 (−8.3 kcal/mol), and MMP9, implicating apoptotic induction and detoxification. From Piper nigrum, piperine exhibited stable binding with BCL2 (−8.5 kcal/mol), AKT1, and STAT3, with supportive QSAR analysis indicating pro-apoptotic effects. Network pharmacology also linked piperine and related alkaloids to MAPK8, RELA, and ESR1, suggesting influence over NF-κB and estrogen pathways. Withania somnifera compounds showed strong anti-cancer interactions as well, with Withaferin A binding hnRNP-K (−9.0 kcal/mol) and demonstrating antiangiogenic potential, while Withanolide D showed robust docking with mTOR (−9.2 kcal/mol) and STAT3 (−8.8 kcal/mol), contributing to cell cycle arrest and suppression of invasion. Collectively, these findings support the multitarget capabilities of plant-derived phytochemicals and reinforce their potential as promising candidates in anticancer drug discovery through molecular docking, dynamics simulations, and network-based modeling (Bhati et al., 2025; Table 2).

Taxanes, particulrly paclitaxel and docetaxel, represent a pivotal class of plant-derived chemotherapeutic agents originally isolated from the bark of Taxus brevifolia and later from Taxus baccata (105) Paclitaxel was the first taxane to be identified and has since been extensively utilized in the treatment of a variety of malignancies. Mechanistically, taxanes exert their antitumor effects by stabilizing microtubules, the structural components essential for cell division (Sati et al., 2024). Unlike other conventional antimitotic drugs that disrupt microtubule formation, paclitaxel and docetaxel promote tubulin polymerization and prevent depolymerization, effectively “freezing” the mitotic spindle in a polymerized state (Abal et al., 2003). This results in mitotic arrest, inhibition of cell division, and eventual induction of apoptosis in rapidly dividing cancer cells.

Clinically, paclitaxel and docetaxel have demonstrated broad-spectrum antineoplastic activity and are widely used in the management of breast cancer, ovarian cancer, non-small cell lung cancer (NSCLC), prostate cancer, and head and neck cancers (Jordan, 2002; Ahmed Khalil et al., 2022). Their efficacy in both adjuvant and metastatic settings has made them a standard part of many chemotherapy regimens. Despite their robust efficacy, these agents are associated with several limitations, including hypersensitivity reactions (due to the solvent Cremophor EL in paclitaxel), neuropathy, myelosuppression, and development of multidrug resistance via P-glycoprotein efflux (Herbst and Khuri, 2003). Thus, taxanes exemplify how natural products can be successfully translated into potent anticancer agents, highlighting the value of phytochemicals in modern oncology.

Vinca alkaloids, primarily vincristine and vinblastine, are among the earliest plant-derived anticancer agents extracted from Catharanthus roseus (Nobili et al., 2012), a plant traditionally used in various folk medicine systems but not explicitly referenced in classical Ayurvedic literature. These alkaloids have significantly advanced cancer chemotherapy due to their unique mechanism of action and potent efficacy against various malignancies. The primary mechanism of action of Vinca alkaloids is their ability to disrupt microtubule dynamics, which are essential for mitosis. Specifically, vincristine and vinblastine bind to tubulin monomers and inhibit their polymerization into microtubules. This inhibition halts mitotic spindle formation, thereby arresting cells in metaphase and leading to apoptosis (Dhyani et al., 2022). Vinca alkaloids selectively target rapidly dividing cells, renders them particularly effective against hematological malignancies.

Vincristine and Vinblastine are integral to many chemotherapy regimens. Vincristine is commonly used in pediatric oncology, and is a key agent in the treatment of acute lymphoblastic leukemia (ALL), Hodgkin’s and non-Hodgkin’s lymphomas, and neuroblastoma (Jordan, 2002; Škubník et al., 2021) In contrast vinblastine is widely used in the management of testicular cancer, Hodgkin’s lymphoma, breast cancer, and Kaposi’s sarcoma (Lopez-Lopez et al., 2016). Their synergistic use with other chemotherapeutics enhances efficacy and minimize the development of drug resistance.

Despite their therapeutic potential, vinca alkaloids present notable challenges. Neurotoxicity, especially peripheral neuropathy, is a dose-limiting side effect of vincristine, while vinblastine is more often associated with myelosuppression (Samuels and Howe, 1970). The potential integration of Ayurvedic approaches with vinca alkaloid-based chemotherapy lies in mitigating side effects and improving patient quality of life.

Podophyllotoxins, particularly etoposide and teniposide, are semi-synthetic derivatives of the natural compound extracted from Podophyllum peltatum (Verstappen et al., 2003; Guerram et al., 2012). These agents belong to the class of epipodophyllotoxins and were developed after identifying the cytotoxic effects of the parent compound podophyllotoxin. The primary mechanism of action of etoposide and teniposide involves inhibition of the enzyme topoisomerase II. This enzyme is essential for DNA replication and cell division as it relieves torsional strain in DNA and stabilize the transient DNA-topoisomerase II complex, preventing the re-ligation of DNA strands (Sharma et al., 2016). This results in persistent DNA breaks, ultimately triggering apoptosis in rapidly dividing cancer cells. The action is cell cycle-specific, most active in the S and G2 phases, making these drugs effective in tumors with high proliferative indices.

Clinically, etoposide is a cornerstone in the treatment of testicular cancer, particularly when combined with cisplatin and bleomycin (Hande, 1998). It is also widely used for small cell lung cancer, lymphomas, and certain leukemias. Teniposide, a closely related compound with a slightly different solubility profile, is predominantly used in pediatric oncology, including acute lymphoblastic leukemia (ALL) and neuroblastoma (Dearnaley et al., 1991). Their efficacy, however, is often tempered by significant toxicities.

Camptothecins, notably irinotecan and topotecan, are potent anticancer agents originally derived from Camptotheca acuminate. These alkaloids were developed following the discovery of camptothecin, a naturally occurring compound that exhibited significant anticancer activity through a novel mechanism of action (Sinkule et al., 1984). Irinotecan and topotecan are semi-synthetic analogs designed to improve solubility and therapeutic efficacy while minimizing toxicity (Gallo et al., 1971).

The primary mechanism of action of camptothecins involves inhibition of DNA topoisomerase I, by inducing single-stranded breaks (Gokduman, 2016). Irinotecan and topotecan stabilize the transient enzyme-DNA complex, preventing re-ligation of the DNA strand ultimately leading to replication fork collapse, DNA damage, and apoptosis. This makes them especially effective against rapidly dividing tumor cells.

Irinotecan is a key component of combination regimens such as FOLFIRI (with 5-fluorouracil and leucovorin) in the treatment of metastatic colorectal cancer (Pommier, 2006). Topotecan is used in the management of ovarian cancer, small cell lung cancer, and as a second-line treatment in cervical cancer (Folprecht et al., 2006). Despite their clinical effectiveness, the use of camptothecins is often limited by significant adverse effects, particularly gastrointestinal toxicity (severe diarrhea) and hematological toxicity (neutropenia).

Other than the above mentioned there are several other exemplary natural compounds which have the anticancer effect. Honokiol, a biphenolic compound extracted from the bark of Magnolia officinalis, modulate multiple molecular targets, such as anti-angiogenic, anti-inflammatory, and pro-apoptotic signalling pathways and inhibits cancer cell proliferation and metastasis (Petrelli et al., 2021). Its lipophilic nature allows it to cross the blood-brain barrier, making it particularly promising in gliomas and brain metastases. Polysaccharide-K (PSK), a protein-bound polysaccharide derived from the medicinal mushroom Trametes versicolor, is another naturally sourced agent approved as an adjuvant therapy for gastric and colorectal cancers (Ong et al., 2019). PSK enhances the immune response by activating dendritic cells, macrophages, and T lymphocytes contributing to improved tumor surveillance. Genistein, a soy-derived isoflavone, represents another compelling natural compound for its anticancer effects, particularly in hormone-sensitive cancers such as breast, prostate, and colon cancers (Habtemariam, 2020). Genistein acts primarily as a tyrosine kinase inhibitor and exerts phytoestrogenic effects by binding to estrogen receptors, particularly ER-β, thereby modulating estrogen signaling. It also interferes with cancer cell growth and metastasis by affecting the PI3K/Akt, Wnt, and MAPK pathways. Furthermore, genistein exhibits antioxidant and anti-inflammatory activities, contributing to its chemopreventive potential (Table 3).

Modern oncology primarily targets cellular and molecular pathways associated with carcinogenesis, employing chemotherapy, radiation, immunotherapy, and targeted agents to inhibit tumor proliferation and metastasis. In contrast, Ayurveda aims to restore dosha balance, strengthen agni (digestive/metabolic fire), and enhance ojas (vitality), all of which contribute to systemic immunity and resilience. () The integration of these paradigms allows for the coupling of tumor-targeted cytotoxicity with systemic support, thereby enhancing treatment tolerance and optimizing patient outcomes. For instance, interventions that support gut health, immune competence, and metabolic detoxification can reduce collateral damage from chemotherapeutic agents, improve treatment adherence, and mitigate long-term side effects.

Several Ayurvedic botanicals have demonstrated significant anti-cancer, immunomodulatory, and chemoprotective activities in both preclinical and clinical settings. Curcuma longa (curcumin), a polyphenolic compound, has shown potent anti-inflammatory (Patel, 2010), antioxidant, and radiosensitizing properties (Saggam et al., 2020) through modulation of oncogenic signaling pathways such as NF-κB, STAT3, and COX-2 (Mishra, 2003; Jurenka, 2009; Sak, 2020). Clinical trials have also indicated that curcumin, when used as an adjuvant with chemotherapeutic agents like paclitaxel and cisplatin (Mohankumar et al., 2021), improves chemosensitivity and mitigates systemic side effects. Similarly, Withania somnifera (ashwagandha), known for its adaptogenic and immunomodulatory properties, has shown efficacy in alleviating fatigue and improving the quality of life (Joshi et al., 2021) in cancer patients undergoing chemotherapy (Lee et al., 2005), with one randomized controlled trial reporting significant improvement among breast cancer patients receiving standardized extracts. Additionally, botanicals such as Tinospora cordifolia and Phyllanthus emblica have exhibited hepatoprotective and antioxidant effects, protecting against hepatic damage and oxidative stress associated with chemotherapy. Piper longum, rich in the alkaloid piperine, has demonstrated the capacity to enhance the oral bioavailability of curcumin and other drugs, serving as a bioenhancer (Hussain et al., 2021). However, despite these promising results, the integration of these botanicals into mainstream oncology is hindered by methodological limitations in existing trials, including small sample sizes, lack of placebo controls, insufficient blinding, and inconsistencies in formulations and dosing protocols. Furthermore, inadequate standardization of phytochemical content and quality control impairs reproducibility across studies. These challenges are compounded by the lack of harmonized regulatory frameworks and tailored clinical guidelines for Ayurvedic interventions.

Conventional cancer treatments (Biswal et al., 2013; Saggam et al., 2020) are frequently associated with adverse effects such as mucositis, gastrointestinal toxicity, fatigue, immunosuppression, and cognitive dysfunction, which can compromise therapy adherence and patient wellbeing (Miller et al., 2008; Cavalcanti et al., 2021). Ayurvedic formulations like Triphala, Shatavari (Asparagus racemosus), and classical Rasayana formulations have been studied for their potential to mitigate such toxicities (dos Santos Guimarães et al., 2013; Andreyev et al., 2012). Triphala (Balasubramani et al., 2011) has demonstrated gastroprotective and antioxidant effects in rodent models of chemotherapy-induced mucositis (Akhtar et al., 2024) while Shatavari has shown mucosal healing and immunoregulatory activity (Peterson et al., 2017). Rasayanas, traditionally used for rejuvenation (Baliga, 2010) and convalescence, may support hematopoietic recovery and improve systemic resilience during and after cytotoxic therapy (Ramnath, 2016; Singh et al., 2018). These interventions should be integrated within a protocolized framework, aligned with treatment timelines and toxicity profiles.

Ayurveda’s incorporation of mind-body practices, including yoga, pranayama, meditation, and mantra therapy (Singh and Rastogi, 2011) aligns with modern psychoneuroimmunology (Gaddipati et al., 2004) models of cancer care. Clinical studies have shown that yoga and meditation reduce cortisol levels, enhance natural killer (NK) cell activity, and improve emotional wellbeing among cancer patients (Vyas et al., 2010; Santra, 2022). The integration of these modalities into oncology rehabilitation programs has been associated with improved treatment tolerance, reduced fatigue, and enhanced quality of life. Ayurvedic mind-body interventions can thus be strategically deployed to buffer the psychological stress and immune suppression (Bauer, 1994) commonly observed during cancer therapy, thereby supporting overall treatment outcomes.

One of Ayurveda’s core principles Prakriti analysis, or assessment of individual constitutional types (Fang et al., 2010) offers a promising parallel to modern precision oncology. Recent developments in Ayurgenomics (Giridharan and Bhana, 2024) have revealed correlations between Prakriti types and genetic, transcriptomic, and metabolic profiles, suggesting a potential framework for personalized integrative care (Huang et al., 2022). Pitta types may exhibit inflammatory tendencies and faster metabolism, possibly influencing drug metabolism and toxicity risk. Combining Prakriti assessment with genomic and biomarker-driven stratification may enhance patient selection for both Ayurvedic and biomedical interventions, allowing for more nuanced, responsive, and individualized cancer care strategies (Luhaste, 2023).

Despite compelling theoretical and preclinical support, the integration of Ayurveda into mainstream oncology requires rigorous scientific validation (Soni, 2025; Madgulwar and Shewalkar, 2024). This includes standardized preclinical models to elucidate pharmacodynamics and synergistic mechanisms, well-designed randomized controlled trials to evaluate clinical efficacy, and comprehensive pharmacovigilance to assess herb-drug interactions (Mukerji and Prasher, 2011). Institutions such as the All India Institute of Medical Sciences (AIIMS), Tata Memorial Centre, and international collaborators have initiated clinical trials exploring Ayurvedic interventions in breast, colorectal, and head and neck cancers. However, broader institutional adoption requires the development of standardized protocols, validated herbal formulations (Sharma et al., 2024) and consensus guidelines that can be integrated into existing oncological pathways (Balkrishna et al., 2024b).

Effective integration hinges on sustained collaboration between Ayurvedic practitioners, oncologists, pharmacologists, and molecular scientists. Such interdisciplinary efforts are essential for designing translational research, co-developing clinical protocols, and training clinicians in integrative care delivery (Mao et al., 2022; Arnold, 2023). Collaborative platforms should also engage regulatory agencies, industry stakeholders, and patient advocacy groups to ensure that integrative oncology evolves as a scientifically robust, ethically governed, and patient-aligned discipline (Mukherjee et al., 2022). Ultimately, this collaborative model will be critical in translating Ayurvedic insights into clinically actionable, evidence-based interventions.

The therapeutic potential of combining Ayurvedic medicine with conventional cancer treatments lies in two interrelated paradigms: synergy and holism. While modern oncologic agents such as taxanes, vinca alkaloids, and platinum compounds focus on targeted cytotoxicity, Ayurvedic interventions emphasize systemic equilibrium, immune modulation, and long-term resilience. Integrating these approaches offers a synergistic effect, wherein Ayurvedic phytochemicals sensitize tumor cells to chemotherapy, mitigate drug resistance, and reduce treatment-related toxicity.

In a phase II randomized, double-blind clinical trial (n = 150), intravenous curcumin combined with paclitaxel significantly improved the objective response rate (ORR: 51% vs. 33%) and reduced fatigue (3 vs. 10 patients; OR 3.7, p = 0.05) compared to paclitaxel alone, without compromising quality of life (Gupta, 2024). Preclinical studies further elucidate that curcumin enhances paclitaxel-induced apoptosis via suppression of NF-κB and activation of caspases, along with modulation of resistance pathways such as PI3K/Akt and STAT3 (Masucci et al., 2025). For instance, curcumin from Curcuma longa has demonstrated synergistic cytotoxicity when combined with paclitaxel and cisplatin, enhancing therapeutic efficacy while reducing systemic inflammation.

Similarly, in an open-label comparative clinical study (n = 100), administration of Withania somnifera (Ashwagandha) extract (2 g every 8 h) during chemotherapy resulted in significantly lower fatigue scores (p < 0.001) and improved functioning across seven domains of the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) (Saghatelyan et al., 2020) Although the observed increase in two-year survival (72% vs. 56%) did not reach statistical significance, the trend supports Ashwagandha’s value in enhancing patient resilience and quality of life during cancer treatment. Withaferin A, a key bioactive constituent, not only potentiates apoptosis in malignant cells but also protects normal tissues from oxidative damage. These effects are mediated through modulation of molecular targets such as NF-κB, PI3K/Akt, and p53, demonstrating the potential of multi-targeted co-therapy in integrative oncology.

Beyond pharmacological synergy, the holistic framework of Ayurveda addresses psycho-oncological dimensions often overlooked in conventional regimens. Rasayana therapies, yoga, pranayama, and personalized dietary interventions based on Prakriti contribute to enhanced mental clarity, immune homeostasis, and overall wellbeing. Clinical studies have reported significant reductions in anxiety, improvements in sleep quality, and enhanced psychological resilience among cancer patients participating in Ayurvedic mind-body interventions (Mustian et al., 2013; Calaf et al., 2018).

The outcomes of such integrative approaches include:

• Enhanced treatment tolerance and reduced drop-out rates during chemotherapy,

These preliminary observations provide a compelling rationale for the development of future clinical trials exploring standardized botanical extracts as adjuvants to chemotherapy and immunotherapy. Systems biology and network pharmacology approaches can facilitate the identification of synergistic interactions, while Ayurgenomic profiling may enable patient stratification for personalized integrative care. Collectively, these efforts can pave the way toward the establishment of evidence-based integrative oncology protocols, forming a scientifically validated alliance between Ayurveda and modern cancer therapeutics.