title: Combined effect of Hsp90 inhibitor geldanamycin and parthenolide via reactive oxygen species-mediated apoptotic process on epithelial ovarian cancer cells.
abstract: Hsp90 inhibitor geldanamycin and parthenolide have been shown to induce apoptosis in cancer cells. However, the combined effect of geldanamycin and parthenolide on epithelial ovarian cancer cells has not been studied. In respect of cell death process, we investigated the promoting effect of parthenolide on geldanamycin-induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Geldanamycin induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels; an increase in Bax and tumour suppressor p53 levels; loss of the mitochondrial transmembrane potential; cytochrome c release; activation of caspases (-8, -9 and -3); cleavage of PARP-1; and increase in the reactive oxygen species formation. Parthenolide enhanced geldanamycin-induced changes in the apoptosis-related protein levels, reactive oxygen species formation, nuclear damage and cell death. The combined effect was inhibited by the addition of oxidant scavengers. The results suggest that parthenolide may potentiate the apoptotic effect of geldanamycin on ovarian carcinoma cell lines by the activation of the caspase-8- and Bid-dependent pathway and the mitochondria-mediated apoptotic pathway. The apoptosis-promoting effect seems to be mediated by the stimulatory effect on the formation of reactive oxygen species.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea. leecs@cau.ac.kr
authors.forename: Chung S
authors.initials: CS
authors.lastname: Lee
authors.forename: Yun J
authors.initials: YJ
authors.lastname: Kim
authors.forename: Seon A
authors.initials: SA
authors.lastname: Lee
authors.forename: Soon C
authors.initials: SC
authors.lastname: Myung
authors.forename: Wonyong
authors.initials: W
authors.lastname: Kim
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C002669:parthenolide; D045304:Cytochromes c; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C001277:geldanamycin