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. IC(50) for 1, 2, and 3 were 0.87, 0.45, and 0.29 ?M (BxPC-3); 1.28, 1.53, and 0.52 ?M (MIAPaCa-2); and 0.59, 2.25, and 0.56 ?M (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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / pathology
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects
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Carcinoma, Pancreatic Ductal / drug therapy*
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Carcinoma, Pancreatic Ductal / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Enzyme Activation
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Gene Expression Profiling
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Glutathione / metabolism*
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Humans
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Mitogen-Activated Protein Kinases / metabolism*
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / pathology
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Polymerase Chain Reaction
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Withanolides / chemistry
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Withanolides / pharmacology*
Substances
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Antineoplastic Agents, Phytogenic
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Withanolides
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Mitogen-Activated Protein Kinases
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Glutathione
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withaferin A