Withaferin A Exerts Cytotoxicity in Single/Multidrug‐Resistant Gastric and Ovarian Cancer Cells and Tumor Xenografts Through the AKT–NF‐κB–STAT3–Survivin Axis

ABSTRACT Resistance to primary chemotherapeutics poses a significant challenge in treating solid tumors. The majority of the second‐line chemo and targeted therapeutics act moderately/less effectively in drug‐resistant tumors owing to the multicausal nature of drug resistance. Therefore, a single agent with pleiotropic effects would be beneficial in combating this adversity. Withania somnifera exhibits multifunctional anticancer properties, but its role in overcoming chemoresistance remains poorly understood. We evaluated the cytotoxic effect of Ashwamax TM ‐ W. somnifera (WS)—extract and Withaferin A (WFA), in intrinsically resistant (KATO‐III and SKOV3) and acquired chemoresistant gastric (AGS 5FU ) and ovarian (A2780 LR ) cancer cellular models. We examined their impact on autophagy and apoptosis pathways and elucidated the underlying molecular mechanism. In vivo efficacy of WFA on cisplatin‐paclitaxel‐resistant epithelial ovarian cancer (EOC) xenografts was assessed using noninvasive optical imaging. Mechanistically, WFA is more proficient in targeting chemoresistant cells than Ashwamax TM ‐WS extract and activates apoptosis by overriding the AKT–NF‐κB–STAT3–survivin axis. Preclinical imaging revealed dose‐dependent tumor regression (during and after treatment) in platinum‐taxol‐resistant EOC xenografts that were unresponsive to cisplatin challenge. WFA, at 3 mg kg −1 dosage, reduced tumor volume by 4.7‐fold compared to controls, with sustained antitumor effects persisting after treatment cessation. WFA effectively targets the AKT–NF‐κB–STAT3–survivin axis to overcome single and multidrug resistance in gastric and epithelial ovarian cancers, presenting a promising therapeutic alternative for chemoresistant malignancies.