2,3-Dihydro-3-methoxywithaferin A

2,3-Dihydro-3beta-methoxy Withaferin-A Protects Normal Cells against Stress: Molecular Evidence of Its Potent Cytoprotective Activity.[Pubmed:29043807]

J Nat Prod. 2017 Oct 27;80(10):2756-2760.

2,3-Dihydro-3beta-methoxy withaferin-A (3betamWi-A) is a natural withanolide that is structurally close to withaferin-A (Wi-A), is cytotoxic to human cancer cells, and is a candidate anticancer natural compound. Using cell-based biochemical, molecular, and imaging assays, we report that Wi-A and 3betamWi-A possess contrasting activities. Whereas Wi-A caused oxidative stress to normal cells, 3betamWi-A was well tolerated at even 10-fold higher concentrations. Furthermore, it promoted survival and protected normal cells against oxidative, UV radiation, and chemical stresses. We provide molecular evidence that 3betamWi-A induces antistress and pro-survival signaling through activation of the pAkt/MAPK pathway. We demonstrate that 3betamWi-A (i) contrary to Wi-A is safe and possesses stress-relieving activity, (ii) when given subsequent to a variety of stress factors including Wi-A, protects normal cells against their toxicity, and (iii) is a vital compound that may guard normal cells against the toxicity associated with various targeted therapeutic regimes in clinical practice.