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Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways
Grogan, Patrick T. Sleder, Kristina D. Samadi, Abbas K. Timmermann, Barbara N. Cohen, Mark S.
Grogan, Patrick T.
Sleder, Kristina D.
Samadi, Abbas K.
Timmermann, Barbara N.
Cohen, Mark S.
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Abstract
Withaferin A (WA), a steroidal lactone derived from the plant Vassobia breviflora, has been reported to have anti-proliferative, pro-apoptotic, and anti-angiogenic properties against cancer growth. In this study, we identified several key underlying mechanisms of anticancer action of WA in glioblastoma cells. WA was found to inhibit proliferation by inducing a dose-dependent G2/M cell cycle arrest and promoting cell death through both intrinsic and extrinsic apoptotic pathways. This was accompanied by an inhibitory shift in the Akt/mTOR signaling pathway which included diminished expression and/or phosphorylation of Akt, mTOR, p70 S6K, and p85 S6K with increased activation of AMPKα and the tumor suppressor tuberin/TSC2. Alterations in proteins of the MAPK pathway and cell surface receptors like EGFR, Her2/ErbB2, and c-Met were also observed. WA induced an N-acetyl-L-cysteinerepressible enhancement in cellular oxidative potential/stress with subsequent induction of a heat shock stress response primarily through HSP70, HSP32, and HSP27 upregulation and HSF1 downregulation. Taken together, we suggest that WA may represent a promising chemotherapeutic candidate in glioblastoma therapy warranting further translational evaluation.
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Date
2013-06
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Springer Verlag
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Keywords
Withaferin A, Glioblastoma multiforme, Oxidative stress, Heat shock response, Akt/mTOR pathway, MAPK pathway
Citation
Grogan, P.T., Sleder, K.D., Samadi, A.K. et al. Invest New Drugs (2013) 31: 545. doi:10.1007/s10637-012-9888-5