Molecular insights into cancer therapeutic effects of the dietary medicinal phytochemical withaferin A.
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 IκB kinase/NF-κB, 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.
Laboratory of Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences,University of Antwerp,Campus Drie Eiken, Universiteitsplein 1, Wilrijk,Belgium.
Chandra Sekhar
CS
Chirumamilla
Laboratory of Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences,University of Antwerp,Campus Drie Eiken, Universiteitsplein 1, Wilrijk,Belgium.
Claudina
C
Pérez-Novo
Laboratory of Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences,University of Antwerp,Campus Drie Eiken, Universiteitsplein 1, Wilrijk,Belgium.
Xaveer
X
Van Ostade
Laboratory of Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences,University of Antwerp,Campus Drie Eiken, Universiteitsplein 1, Wilrijk,Belgium.
Wim
W
Vanden Berghe
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D064209:Phytochemicals / Q000494:pharmacology*; D011487:Protein Conformation; D054358:Withanolides / Q000494:pharmacology*
D064209:Phytochemicals; D054358:Withanolides; C009684:withaferin A
 AKT protein kinase B;  CDK cyclin-dependent kinases;  EFGR epidermal growth factor receptor;  ERK extracellular signal-regulated kinase;  HSP heat shock protein;  IKK IκB kinase;  MAPK mitogen-activated protein kinase;  PI3K PI3 kinase;  RSK ribosomal S6 kinase;  WA withaferin A; Cancer; Covalent kinase inhibitor; Cysteinome; Withaferin A