Molecular mechanisms of trenimon-induced cytotoxicity in resistant L5178Y/HBM10 cells.
L5178Y/HBM10 lymphoblasts, resistant to a model quinone antitumor agent, hydrolyzed benzoquinone mustard, were approximately 2-fold more sensitive to trenimon (2,3,5-tris-ethyleneimino-1,4-benzoquinone) compared to parental cells (L5178Y). The L5178Y/HBM10 cells are reported to have a 24-fold increased level of DT-diaphorase activity over the parental cells. Inhibition of DT-diaphorase by dicoumarol markedly inhibited the cytotoxic activity of trenimon to the resistant L5178Y/HBM10 cells. Spectrophotometric analysis of the reduction of the quinone, trenimon, to its hydroquinone form was shown to occur approximately 25 times more rapidly in the L5178Y/HBM10 cells relative to the parental cells and was inhibited by discoumarol. Trenimon also induced continuous cyanide-resistant respiration in the L5178Y cells, but not in the resistant L5178Y/HBM10 cells. This suggested a one-electron reduction of trenimon to a semiquinone free radical which could then redox cycle with oxygen in the L5178Y cells. However, in the presence of dicoumarol the resistant L5178Y/HBM10 cells induced similar oxygen activation to the parental cells. Dicoumarol had no effect on trenimon-induced cyanide resistant respiration in the parental cells. These findings suggest that the two-electron reduction of trenimon to its hydroquinone derivative plays a major role in the cytotoxic activity of trenimon.
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
J M
JM
Silva
P J
PJ
O'Brien
D002470:Cell Survival / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D004351:Drug Resistance; D066298:In Vitro Techniques; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D014228:Triaziquone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); D014228:Triaziquone