The review, led by researchers from Ahmadu Bello University, Adeleke University, Babcock University, and collaborating Nigerian institutions, synthesizes preclinical, epidemiological, and emerging clinical evidence for six structurally distinct classes of plant-derived compounds: alkaloids, flavonoids, terpenoids, polyphenols, coumarins, and organosulfur compounds. These phytochemicals modulate multiple oncogenic pathways relevant to gynecological malignancies, including tumor cell proliferation, intrinsic and extrinsic apoptosis, angiogenesis, oxidative stress, inflammation, hormone receptor signaling, HPV E6/E7 oncoprotein expression, and epigenetic regulation. The authors argue that the breadth of mechanistic activity—rather than a single molecular target—distinguishes plant-derived interventions from many conventional cytotoxic agents and may explain their potential to complement standard therapies.

Paclitaxel, a taxane terpenoid isolated from the bark of Taxus brevifolia, serves as the definitive proof of concept that plant-derived compounds can achieve gold-standard clinical status in gynecological oncology. Paclitaxel stabilizes polymerized microtubules, arrests dividing cells in G2/M phase, and phosphorylates Bcl-2 to trigger apoptosis. In combination with carboplatin, it is the standard of care worldwide for advanced ovarian cancer, with a reported five-year overall survival of approximately 45 percent. Topotecan, a semi-synthetic derivative of the alkaloid camptothecin, inhibits topoisomerase I and holds regulatory approval for platinum-resistant recurrent ovarian cancer and advanced cervical cancer, based on data from Phase II/III trials including the GOG-179 study. Vincristine and vinblastine, derived from Catharanthus roseus, arrest ovarian and cervical cancer cells through beta-tubulin binding, though dose-limiting neurotoxicity restricts their use as single agents.

Among non-approved phytochemicals, the review highlights several with compelling preclinical activity. Berberine, a protoberberine alkaloid from Berberis vulgaris, inhibits proliferation and promotes apoptosis in Ishikawa endometrial carcinoma cells through modulation of PI3K/AKT signaling, with concurrent AMPK activation and NF-κB inhibition. Quercetin induces mitochondrial membrane depolarization, cytochrome c release, and caspase-3/9 activation in SKOV-3 and A2780 ovarian cancer cells while suppressing VEGF transcription in HeLa cervical cancer cells. Apigenin induces caspase-dependent apoptosis and PARP cleavage in HeLa cells and, distinctively, suppresses HPV E6/E7 oncoprotein expression—targeting the viral driver of cervical carcinogenesis rather than only downstream oncogenic effects. Kaempferol inhibits STAT3 phosphorylation and restores p53 function in cisplatin-resistant ovarian cancer cells, a mechanistically important observation given that constitutive STAT3 activation is a well-characterized driver of platinum resistance.

Polyphenols such as curcumin, resveratrol, and epigallocatechin-3-gallate (EGCG) show particular promise. Curcumin suppresses NF-κB, AP-1, and COX-2, shifts Bax/Bcl-2 ratios toward apoptosis, and downregulates HPV E6 and E7 in cervical cancer cell lines. In combination with tanshinone IIA, curcumin inhibits HPV-positive W12 cervical precancer cells at sub-IC50 doses of each agent alone. Resveratrol activates SIRT1 and inhibits PI3K/AKT/mTOR signaling, restoring taxane sensitivity in paclitaxel-resistant ovarian cancer cell lines. EGCG inhibits DNMT1, DNMT3a, and DNMT3b, reactivating silenced tumor suppressor genes through epigenetic reprogramming. The strongest clinical signal among non-approved compounds comes from EGCG in cervical precancer: a Phase II randomized trial reported 69 percent histologically confirmed regression of CIN 2/3 lesions with oral and topical EGCG at 200 mg per day, compared with 10 percent in placebo controls.

Hormone receptor modulation represents another mechanistic frontier. Soy-derived isoflavones genistein and daidzein bind estrogen receptor beta with higher affinity than estrogen receptor alpha, opposing ER-alpha-mediated proliferative signaling in the endometrium. In mice, dietary genistein and daidzein significantly reduced the incidence of endometrial adenocarcinoma and atypical hyperplasia. A meta-analysis of ten observational studies reported a 49 percent reduction in ovarian cancer risk with higher phytoestrogen intake (RR 0.51, 95% CI 0.38–0.69). The authors caution, however, that the net estrogenic or anti-estrogenic effect of phytoestrogens depends on ambient estrogen levels, receptor subtype ratios, and cancer molecular subtype, producing conflicting results across different in vitro systems that must inform patient stratification in future trials.

Coumarins and organosulfur compounds round out the mechanistic landscape. Auraptene and scopoletin exert anti-invasive and anti-proliferative effects in ovarian and endometrial cancer cells through combined inhibition of PI3K/AKT/mTOR signaling and matrix metalloproteinase activity. Importantly, coumarin derivatives demonstrate the capacity to reverse P-glycoprotein-mediated multidrug resistance—a critical contributor to platinum and taxane resistance in ovarian cancer—through direct P-gp inhibition. Allicin and related organosulfur compounds from garlic induce apoptosis in ovarian and endometrial cancer cells through ROS generation, Nrf2 pathway activation, and Bax/Bcl-2 ratio modulation, with anti-migratory effects documented through suppression of MMP-2 and MMP-9 gelatinase activity.

Poor oral bioavailability remains the most significant obstacle to clinical translation for most non-approved phytochemicals. Curcumin has oral bioavailability below 1 percent in unformulated form due to rapid intestinal and hepatic phase II metabolism, primarily glucuronidation and sulfation. EGCG undergoes catechol-O-methyltransferase-mediated methylation, substantially reducing systemic stability. Resveratrol exhibits rapid first-pass metabolism with a plasma half-life ranging from minutes to low hours. Nanoformulation strategies directly address these limitations: liposomal encapsulation improves aqueous solubility and protects compounds from presystemic metabolism, PLGA biodegradable nanoparticles provide sustained drug release, and phytosomes enhance membrane permeability. Co-administration of piperine inhibits intestinal glucuronidation and modulates efflux transporters, resulting in approximately 20-fold increases in curcumin area under the curve in human volunteer studies. Nab-paclitaxel, an albumin-bound nanoparticle formulation of paclitaxel, provides a clinically validated regulatory precedent for nanoformulated phytochemical therapeutics.

The review identifies critical barriers limiting clinical translation: botanical preparations are unstandardized, randomized trial data in gynecological cancer populations are scarce, and herb-drug interaction profiles are incompletely characterized. EGCG inhibits CYP3A4 and CYP2C9 enzymes affecting paclitaxel, cyclophosphamide, and tamoxifen metabolism; piperine broadly inhibits P-gp and other CYP isoforms, potentially increasing plasma levels of co-administered chemotherapy. High-dose isoflavone supplementation in women taking hormonal therapy for ER-positive endometrial or ovarian cancer is not currently supported by evidence. The authors call for biomarker-embedded Phase II randomized trials with pharmacokinetic sampling, molecular subtype-stratified patient selection, and rigorous evaluation of phytochemical-chemotherapy combination regimens. Precision medicine strategies—such as identifying KEAP1/NRF2-mutant ovarian tumors responsive to phytochemical-mediated oxidative stress modulators, or high-DNMT1 cervical cancers sensitive to epigenetic reprogramming—could significantly enhance the signal-to-noise ratio of future clinical trials.

Subject of Research: Health & Medicine

Article Title: Impact of plant-based interventions on gynecological cancers: a narrative review of mechanistic interplays and clinical evidence

Article References: Fabrael, F. B., Sotunsa, J., Olaniyi, K. S., Oghenetega, O. B., Adewale, O., Akindele, B. M., Olanrewaju, F., Gbimadee, N. L., Olayemi, S., Bolaji, A. O., Iyobhebhe, M. O., Adegbotoluwa, E. M., Folahanmi, E. D., Kaisar, J. A., & Oyedokun, P. A. (2026). Impact of plant-based interventions on gynecological cancers: a narrative review of mechanistic interplays and clinical evidence. Frontiers in Molecular Medicine, 6, Article 1832188. https://doi.org/10.3389/fmmed.2026.1832188

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1832188

Keywords: gynecological cancers, phytochemicals, paclitaxel, curcumin, EGCG, HPV, nanoformulation, chemoresistance, Frontiers in Molecular Medicine, Impact, plant-based, interventions