Mechanistic Insights into Withanolides Action Against Cancer

Withania somnifera (Ashwagandha), also known as Indian ginseng, is a well-known herb of Ayurveda. It is commonly used in herbal formulations to increase energy and stamina, improve overall health and have also been reported to be beneficial against inflammation, stress, aging, immune-response and cancer. The molecular mechanism of action of this herb against various diseases is still not yet fully understood. Withanolides, extracted from Withania somnifera, mainly Withaferin-A (Wi-A) and Withanone (Wi-N), are steroidal compounds having a lactone backbone, have shown selective killing of the cancer cells. From the past few years, our lab has tried to elucidate the molecular mechanism of action of withanolides against cancer cells using computational tools and cancer cell-based assays. Wi-N shows inhibition of STK15 (Aurora-A kinase gene) signalling by inhibiting the binding of TPX2 with STK15. Wi-N also binds to mortalin and disrupts the mortalin-p53 complex and promotes the translocation of p53 into the nucleus. Furthermore, the combination of Wi-N and Wi-A has shown to interfere with the binding of heterogenous ribonucleoprotein with ssDNA/RNA to reduce the expression of crucial cancer driver modules. These include matrix metalloproteinases, vascular endothelial growth factors, and extracellular signal-regulated kinases responsible for metastasis and invasion of cancer cells. While Wi-A alone has shown the activation of IKB-NFkB signalling and decreased expression of Cyclin D1 and CDKs, Wi-A has also shown inhibitory activity against Alternate Lengthening of Telomerase by downregulation of MRN (Mre11, Rad50, Nbs1) complex and inducing G2/M arrest and apoptotic signalling. The overall studies till now suggest that withanolides induce apoptosis, senescence, reduce metastasis and angiogenesis by targeting cell cycle regulatory proteins directly or the proteins upstream to them.