Sensitization of U937 Cells to Heat Shock by Oxalomalate, a Competitive Inhibitor of NADP+-dependent Isocitrate Dehydrogenase

Abstract

Heat shock may increase oxidative stress due to increased production of reactive oxygen species (ROS) and/or the promotion of cellular oxidation events. Cytosolic NADP+-dependent isocitrate dehydrogenase (ICDH) in U937 cells produces NADPH, an essential reducing equivalent for the antioxidant system. The protective role of ICDH against heat shock in U937 cells was investigated in control and cells treated with oxlalomalate, a competitive inhibitor of ICDH. Upon exposure to heat shock, the viability was lower and the protein oxidation, lipid peroxidation and oxidative DNA damage were higher in oxalomalate-treated cells as compared to control cells. We also observed the significant increase in the endogenous production of ROS, as measured by the oxidation of 2'7'-dichlorodihydrofluorescin in U937 cells treated with oxalomalate. These results suggest that ICDH plays an important role as an antioxidant defense enzyme in cellular defense against heat shock through the removal of ROS.

Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration

“…Studies have indicated a decrease in IDH activity after OMA treatment, resulting in reduced plasma triglyceride and cholesterol levels and adipocyte lipoprotein lipase activity, suggesting a possible inhibitory role of OMA in fat accumulation [41]. Apart from its lipid-lowering effects, OMA has several other effects, such as enhanced apoptotic cell death in cancer cells, and an inhibitory effect on the LPS-induced inflammatory response through the induction of intracellular ROS accumulation [42], [43], [44], [45]. However, to the best of our knowledge, there is no information available regarding the effects of OMA on CNV in AMD.…”