Withaferin A

Withaferin A is a steroidal lactone that has been found in W. somnifera with diverse biological activities.^1,2 It binds to and induces aggregation of vimentin intermediate filaments in cultured endothelial cells and fibroblasts, inducing apoptosis when used at concentrations ranging from 2 to 25 μM. It also induces formation of perinuclear aggregates in other intermediate filament networks including peripherin, neurofilament-triplet protein, and keratin as well as disrupts the organization of microtubules and actin/microfilaments.² Withaferin A induces noncanonical ferroptosis via induction of lipid peroxidation through interaction with Kelch-like ECH-associated protein 1 (KEAP1) in IMR-32 neuroblastoma cells, an effect that is blocked by the ferroptosis inhibitors ciclopirox olamine and ferrostatin-1 (Item No. 17729).³ It also binds to and inhibits glutathione peroxidase 4 (GPX4) in IMR-32 cells. In vivo, withaferin A (4 mg/kg) reduces intratumor GPX4 expression and induces tumor regression in an IMR-32 mouse xenograft model. Withaferin A (2 mg/kg) also inhibits angiogenesis in a mouse model of injury-induced corneal neovascularization.¹

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1. Bargagna-Mohan, P., Hamza, A., Kim, Y.e., et al. The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin. Chem. Biol. 14(6), 623-634 (2007).

2. Grin, B., Mahammad, S., Wedig, T., et al. Withaferin A alters intermediate filament organization, cell shape and behavior. PLoS One 7(6), 1-13 (2012).

3. Hassannia, B., Wiernicki, B., Ingold, I., et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J. Clin. Invest. 128(8), 3341-3355 (2018).