Journal
PROCEEDINGS OF THE NUTRITION SOCIETY
Volume 76, Issue 2, Pages 96-105Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0029665116002937
Keywords
Withaferin A; Cancer; Cysteinome; Covalent kinase inhibitor
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Funding
- Strategic Basic Research grant of the Agency for Innovation by Science and Technology (IWT, Belgium), FWO [G059713N, G079614N]
- NOI/DOCPRO (UA)
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Despite the worldwide research efforts to combat cancer, it remains a leading cause of death. Although various specific kinase inhibitors already have been approved for clinical cancer treatment, occurrence of intrinsic or acquired resistance and intermittent response over longer periods limits long-term success of single kinase-targeted therapies. In this respect, there is a renewed interest in polypharmaceutical natural compounds, which simultaneously target various hyperactivated kinases involved in tumour-inflammation, angiogenesis, cell survival, proliferation, metastasis and angiogenesis. The dietary medicinal phytochemical withaferin A (WA), isolated from Withaferin somnifera (popular Indian name Ashwagandha), holds promise as a novel anti-cancer agent, which targets multiple cell survival kinase pathways, including IB kinase/NF-B, PI3 kinase/protein kinase B/mammalian target of rapamycin and mitogen-activated protein kinase/extracellular signal-regulated kinase amongst others. In this review, we propose a novel mechanism of WA-dependent kinase inhibition via electrophilic covalent targeting of cysteine residues in conserved kinase activation domains (kinase cysteinome), which could underlie its pleiotropic therapeutic effects in cancer signalling.
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