Induction of apoptotic cell death by methylglyoxal and 3-deoxyglucosone in macrophage-derived cell lines

Production of 2-oxoaldehyde compounds increase during hyperglycemic conditions and is cytotoxic to susceptible cells. We have investigated the effects of methylglyoxal and 3-deoxyglucosone at physiological concentrations on monocytic leukemia U937 cells and other cell lines. Both ladder formation of DNA and nuclear fragmentation were observed in the cells treated with these agents, indicating that apoptotic cell death was induced. The fluorescent intensity of an oxidation sensitive dye (2',7'-dichlorofluorescin) was increased in U937 cells but not in other cells in which apoptosis was not induced. The levels of intracellular glutathione, however, were only slightly changed. Apoptosis and intracellular oxidant levels were enhanced by buthionine sulfoximine, an inhibitor of glutathione biosynthesis, and partially blocked by N-acetylcysteine, an antioxidant. Thus, it is conceivable that elevation of intracellular oxidant stress is a cause of the apoptosis induced by cytotoxic 2-oxoaldehyde compounds.