title: 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. 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.
authors.affiliation: Cancer Center, University of Arizona, Tucson, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Liu
authors.forename: Wenqing
authors.initials: W
authors.lastname: Qi
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Cooke
authors.forename: E M
authors.initials: EM
authors.lastname: Kithsiri Wijeratne
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Xu
authors.forename: Marilyn T
authors.initials: MT
authors.lastname: Marron
authors.forename: A A
authors.initials: AA
authors.lastname: Leslie Gunatilaka
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016133:Polymerase Chain Reaction; D054358:Withanolides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054358:Withanolides; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; C009684:withaferin A