We previously reported that MSTO-211H cells have a highercapacity to regulate Nrf2 activation in response to changes inthe cellular redox environment. To further characterize itsbiological significance, the response of Nrf2, a transcriptionfactor that regulates ARE-containing genes, on the synergisticcytotoxic effect of clofarabine and resveratrol was investigatedin mesothelioma cells. The combination treatment showed amarked growth-inhibitory effect, which was accompanied bysuppression of Nrf2 activation and decreased expression ofheme oxygenase-1 (HO-1). While transient overexpression ofNrf2 conferred protection against the cytotoxicity caused bytheir combination, knockdown of Nrf2 expression using siRNAenhanced their cytotoxic effect. Pretreatment with Ly294002, aPI3K inhibitor, augmented the decrease in HO-1 level by theircombination, whereas no obvious changes were observed inNrf2 levels. Altogether, these results suggest that the synergisticcytotoxic effect of clofarabine and resveratrol was mediated, atleast in part, through suppression of Nrf2 signaling.