A Study to Identify a Potent Withanolide From Withania somnifera Targeting Bcl-2 Family Proteins in Cervical Cancer Through In Silico and In Vitro Approach

Background: Natural compounds remain a vital reservoir of novel drug candidates because of their structural diversity and therapeutic potential for managing cancer and drug-resistant infectious diseases. Attention has increasingly focused on medicinal plants and related natural sources for preventing and treating various human cancers. Cervical cancer represents the fourth most frequently diagnosed malignancy among women worldwide. The therapeutic effectiveness of natural products in cervical cancer may be further enhanced by precisely targeting key molecular pathways involved in disease progression. Methods: This study used molecular docking and in vitro analyses to investigate the potential anticancer effects of Withania somnifera withanolides by inducing apoptosis in cervical cancer cells. Additionally, the pharmacokinetic behavior of selected compounds was predicted through Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) and drug-likeness analyses. Results: The results showed strong binding affinity for the B-cell lymphoma 2 (Bcl-2) family anti-apoptotic proteins, favorable ADMET properties, and selection of the more potent withanolide, withanolide A, for further analysis. In vitro evaluation revealed a dose- and time-dependent reduction in cell viability in withanolide A-treated CaSki cells, with significant induction of early and late apoptosis. Gene expression analysis showed dose-dependent downregulation of anti-apoptotic genes (Myeloid Cell Leukemia 1 (MCL-1), BCL2-like 10 (BCL2L10), BCL-2 and BCL2-like 1 (BCL2L1)), suggesting activation of the intrinsic apoptotic pathway. Conclusion: The current study suggests that withanolide A may function as a promising apoptosis-inducing agent targeting Bcl-2 family proteins. Furthermore, in vivo validation and mechanistic studies are needed to support its development as a potential anti-cervical cancer therapeutic.