Glyoxalase I is involved in resistance of human leukemia cells to antitumor agent-induced apoptosis.

Abnormality in the machinery of apoptosis is associated with a resistant phenotype of the tumor cell to chemotherapy. To determine the molecular basis of resistance to antitumor agent-induced apoptosis, we performed a complementary DNA (cDNA) subtractive hybridization with messenger RNA (mRNA) from human monocytic leukemia U937 and its variant UK711, which is resistant to apoptosis induced by antitumor agents. We found that glyoxalase I (GLO1), an enzyme that detoxifies methylglyoxal, is selectively overexpressed in the apoptosis-resistant UK711 cells. The GLO1 enzyme activity was significantly elevated in UK711 and UK110 cells, another drug-resistant mutant, as well as in K562/ADM, adriamycin-resistant leukemia cells, compared with their parental cells. When overexpressed in human Jurkat cells, GLO1 inhibited etoposide- and adriamycin-induced caspase activation and apoptosis, indicating the involvement of GLO1 in apoptosis suppression caused by these drugs. Moreover, cotreatment with S-p-bromobenzylglutathione cyclopentyl diester (BBGC), a cell-permeable inhibitor of GLO1, enhanced etoposide-induced apoptosis in resistant UK711 cells but not in parental U937 cells. Taken together, these results indicate that GLO1 is a resistant factor to antitumor agent-induced apoptosis in human leukemia cells and that the GLO1 inhibitor could be a drug resistance-reversing agent.