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3beta-Methoxy Derivation of Withaferin-a Attenuates its Anticancer Potency: Bioinformatics and Molecular Evidences

Huang C, Vaishnavi K, Kalra RS, Zhang Z, Sekar K, Kaul SC and Wadhwa R

Withaferin A (Wi-A), a potent anticancer withanolide extracted from Withania somnifera- a tropical medicinal plant, was earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells causing either growth arrest or apoptosis. In view of the information that alkyl derivatives of several bioactive steroidal compounds exhibit improved stability and activity through mechanisms that have not been completely understood, we investigated the effect of Withaferin A and its methoxy-derivative (2,3-dihydro-3- methoxy-Withaferin A) on human cancer cells to analyze the molecular interactions and efficacy. Systematic bioinformatics and molecular experimental approaches comprising expression analysis and imaging techniques were employed to demonstrate the interactions of Withaferin A and 3β-methoxy Withaferin A with their molecular targets. We demonstrate that 3β-methoxy derivation of Withaferin A possess weaker docking potential to its molecular targets and therefore possess attenuated anticancer activity as compared to Withaferin A, and was affirmed by a number of biochemical and in vitro experiments. Based on the Bioinformatics and experimental data we report that the 3β-methoxy derivation of Withaferin A attenuates its anticancer activities, and hence sufficient care is warranted in the use of these phytochemicals as anticancer reagents.