title: Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation.
abstract: We previously reported that MSTO-211H cells have a higher capacity to regulate Nrf2 activation in response to changes in the cellular redox environment. To further characterize its biological significance, the response of Nrf2, a transcription factor that regulates ARE-containing genes, on the synergistic cytotoxic effect of clofarabine and resveratrol was investigated in mesothelioma cells. The combination treatment showed a marked growth-inhibitory effect, which was accompanied by suppression of Nrf2 activation and decreased expression of heme oxygenase-1 (HO-1). While transient overexpression of Nrf2 conferred protection against the cytotoxicity caused by their combination, knockdown of Nrf2 expression using siRNA enhanced their cytotoxic effect. Pretreatment with Ly294002, a PI3K inhibitor, augmented the decrease in HO-1 level by their combination, whereas no obvious changes were observed in Nrf2 levels. Altogether, these results suggest that the synergistic cytotoxic effect of clofarabine and resveratrol was mediated, at least in part, through suppression of Nrf2 signaling.
authors.affiliation: Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University, Cheonan 330-090, Korea.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Im
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.forename: Ji-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Seong Youn
authors.initials: SY
authors.lastname: Won
authors.forename: Moon-Kyun
authors.initials: MK
authors.lastname: Cho
authors.forename: Hae-Seon
authors.initials: HS
authors.lastname: Nam
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sang-Han
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001087:Arabinonucleosides / Q000008:administration & dosage; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D000077866:Clofarabine; D015536:Down-Regulation; D004357:Drug Synergism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D013267:Stilbenes; D000077866:Clofarabine; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol