Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways.

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-cysteine-repressible 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.

• Authors: Patrick T Grogan, Kristina D Sleder, Abbas K Samadi, Huaping Zhang, Barbara N Timmermann, Mark S Cohen
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 3 Pg. 545-57 (Jun 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 23129310 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA-Binding Proteins
• HSF1 protein, human
• Heat Shock Transcription Factors
• Heat-Shock Proteins
• Reactive Oxygen Species
• Transcription Factors
• Withanolides
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• withaferin A

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA-Binding Proteins
• Glioblastoma (metabolism)
• Heat Shock Transcription Factors
• Heat-Shock Proteins (metabolism)
• Heat-Shock Response (drug effects)
• Humans
• Mice
• Oxidative Stress
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Transcription Factors
• Withanolides (pharmacology)