Ex vivo drug sensitivity and in silico evaluation of phytochemicals in gynaecological cancers

Background: Gynaecological cancers-including cervical, ovarian, endometrial, and vulvar cancers-pose significant therapeutic challenges due to late-stage diagnosis, therapeutic resistance, and the presence of cancer stem cells. Dietary phytochemicals are emerging as potential modulators of cancer-related pathways, but their clinical utility is often limited by poor pharmacokinetics. Integrating in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling, molecular docking, and ex vivo drug sensitivity screening may facilitate the identification of effective therapies. Methods: Primary tumor cells were isolated from 22 patients (age range 29-83 years) undergoing surgery for cervical (n=13), ovarian (n=2), endometrial/uterine (n=4), and vulvar (n=3) cancers. Cell yields ranged from 15.9 ×10⁶ to 3.05 ×10⁹ with viability between 14-99%. Cells were cryopreserved for downstream assays. Six dietary phytochemicals (quercetin, curcumin, resveratrol, EGCG, genistein, ursolic acid) were evaluated using SwissADME and pkCSM to predict pharmacokinetic and toxicity profiles. Boiled-egg plots assessed gastrointestinal absorption and blood-brain barrier permeability. Molecular docking was performed against key enzymes implicated in gynecological cancer pathways (EGFR, VEGFR-2, PI3K, TOP2A) using AutoDock Vina. Ex vivo drug sensitivity screening compared FDA-approved chemotherapeutics with the selected phytochemicals to identify compounds with higher cytotoxic potential. Results: ADMET profiling revealed high gastrointestinal absorption for quercetin, curcumin, resveratrol, and genistein (HIA 77-93%), with limited BBB penetration except for resveratrol. Ursolic acid and EGCG demonstrated poor absorption. P-glycoprotein efflux and CYP inhibition were minimal for most compounds, though EGCG showed hERG II inhibition, and ursolic acid presented hepatotoxicity risk. Molecular docking showed favorable binding of EGCG to EGFR (-9.3 kcal/mol), curcumin to VEGFR-2 (-9.4 kcal/mol), and ursolic acid to TOP2A (-9.1 kcal/mol), comparable to FDA-approved inhibitors. Preliminary ex vivo drug screening indicated that FDA-approved chemotherapeutics exhibited higher cytotoxicity across patient-derived cells compared to the dietary phytochemicals. Conclusions and Future Directions: Our integrated approach demonstrates that ex vivo drug sensitivity screening complements in silico ADMET and molecular docking, providing a platform to prioritize therapeutic candidates. Preliminary data suggest FDA-approved chemotherapeutics outperform dietary phytochemicals in patient-derived models. Future work will incorporate biostatistical and genomic analyses to predict optimal drug combinations for individualized therapy, potentially enabling precision oncology strategies for gynecological cancers.