An Analog of Withaferin A Activates the MAPK and Glutathione "Stress" Pathways and Inhibits Pancreatic Cancer Cell Proliferation

• Published in: Cancer investigation Vol. 29; no. 10; pp. 668 - 675
• Main Authors: Liu, Xiaobing, Qi, Wenqing, Cooke, Laurence S., Kithsiri Wijeratne, E. M., Xu, Ya-ming, Marron, Marilyn T., Leslie Gunatilaka, A. A., Mahadevan, Daruka
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 15.11.2011; Taylor & Francis
• Subjects: 4,27-Diacetyl-4-epi-withaferin A; 4-Epi-withaferin A; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Enzyme Activation; Gene Expression Profiling; Glutathione - metabolism; Glutathione pathway; Humans; MAPK; Mitogen-Activated Protein Kinases - metabolism; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Polymerase Chain Reaction; Withaferin A; Withanolides - chemistry; Withanolides - pharmacology
• ISSN: 0735-7907; 1532-4192
• DOI: 10.3109/07357907.2011.626478

Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC50 for 1, 2, and 3 were 0.87, 0.45, and 0.29 μM (BxPC-3); 1.28, 1.53, and 0.52 μM (MIAPaCa-2); and 0.59, 2.25, and 0.56 μM (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose- and time-dependent apoptosis, activates MAPK and glutathione "stress" pathways, and inhibits proliferation.