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

Abstract

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.

Keywords: :

• Withaferin A (1)
• 4-Epi-withaferin A (2)
• 4,27-Diacetyl-4-epi-withaferin A (3)
• Pancreatic cancer
• Apoptosis
• Gene expression profiling
• Glutathione pathway
• MAPK