Withanone as an inhibitor of survivin: A potential drug candidate for cancer therapy

• Survivin, an inhibitor of apoptosis, is highly expressed in almost all cancer.
• Survivin binds with caspases and inhibits them, which results into inhibition of cancer.
• Survivin also play important role in mitosis–cell proliferation.
• Withanone, a botanical, has shown anti-proliferative activity and induction of apoptosis in cancer cells.
• Present study elucidate the mechanism by which withanone neutralizes the role of survivin in inhibition of apoptosis and cell division.

Survivin, the smallest inhibitor of apoptosis protein, which has been reported to be highly expressed in almost all known cancers, plays a dual role in survival as well as the proliferation of cancer cells. It inhibits apoptosis by inhibiting caspases as well as facilitating mitosis by becoming a part of chromosomal passenger complex through its BIR5 domain. Docking studies carried out with herbal ligand withanone derived from roots of Withania somnifera have shown strong binding affinity of −19.1088 kJ/mol with BIR5 domain of survivin and in turn interferes with inhibitory action against caspases and may lead to apoptosis. Binding of withanone at BIR5 domain of survivin may also interfere with chromosomal passenger complex and lead to halt the mitotic process within the cancer cell. Docking studies support various experimental outcomes and suggest withanone as a potential candidate molecule in cancer therapy.

(A) In normal cells, under unfavourable conditions, mitochondria release Smac/DIABLO, which binds to BIR domain of IAPs. Thus IAPs could not inhibit procaspases and cell undergo apoptosis. (B) In almost all type of cancers, Survivin, a novel IAP is highly expressed and may be engaged with most of Smac/DIABLO molecules by interacting with its BIR5 domain. This may result in leaving several IAPs free to interact and inhibit procaspases, caspase 9, caspase 3 and caspase 7 resulting into inhibition of apoptosis. Survivin molecules also become component of chromosomal passenger complex and drive cells to mitosis. (C) Withanone, a herbal ligand, binds with BIR5 domain of survivin and interfere with Smac/DIABLO leading to caspase inhibition. Its presence increase the probability of free Smac/DIABLO molecule to inhibit IAPs including survivin. The presence of withanone thus may drive cell to undergo apoptosis.Figure optionsDownload as PowerPoint slide