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http://dx.doi.org/10.5483/BMBRep.2012.45.11.111

Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation  

Lee, Yoon-Jin (Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University)
Im, Jae-Hyuk (Department of Biochemistry, College of Medicine, Soonchunhyang University)
Lee, David M. (Cell Biology and Genetics in Biological Sciences, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park)
Park, Ji-Sung (Department of Biochemistry, College of Medicine, Soonchunhyang University)
Won, Seong Youn (Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University)
Cho, Moon-Kyun (Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University)
Nam, Hae-Seon (Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University)
Lee, Yong-Jin (Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University)
Lee, Sang-Han (Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University)
Publication Information
BMB Reports / v.45, no.11, 2012 , pp. 647-652 More about this Journal
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.
Keywords
Chemoresistance; Clofarabine; Mesothelioma; Nrf2; Resveratrol;
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