Lazaroid compounds prevent early but not late stages of oxidant-induced cell injury: Potential explanation for the lack of efficacy of lazaroids in clinical trials

Earlier in vitro studies demonstrated the remarkable potency of the lazaroi d compounds to prevent oxidant-induced early cell injury. However, the abil ity of lazaroid compounds to limit oxidative injury in vivo (including rena l ischemia-reperfusion) has been less certain, and the early clinical trial s using lazaroids to limit CNS injury or organ injury in the setting of tra nsplantation have not been promising. Lazaroid compounds are potent inhibit ors of lipid peroxidation, and their inability to influence other key injur y processes, particularly during the late stages of cell injury, might part ly explain the limited clinical efficacy. To test this, renal tubular (LLC- PK1) cells were incubated with 250 muM H2O2 for 135 min, in the presence or absence of 2-methyl aminochroman (2-MAC, U-83836E), a lazaroid with potent ability to inhibit lipid peroxidation, or desferrioxamine, (DFO) an iron c helator with broader antioxidant efficacy. Cell injury, lipid peroxidation, DNA damage and ATP depletion were measured in the early (immediately after H2O2 incubation) and late (24 h after H2O2 incubation) stages of cell inju ry. In the early stage, 2-MAC suppressed H2O2-induced lipid peroxidation an d LDH release, but not the DNA damage, ATP depletion or loss of cell replic ation. In contrast, DFO suppressed all of the measurements. In the late sta ges, despite continued suppression of lipid peroxidation, only DFO maintain ed significant cytoprotection against H2O2, and this was accompanied by red uced DNA damage, higher ATP levels and preservation of cell proliferation. Thus, the inability of the lazaroid compound 2-MAC to sustain cytoprotectio n in the later stages of cell injury might provide at least a partial expla nation for the inefficiency of lazaroids to limit tissue injury in clinical and certain in vivo settings. (C) 2001 Academic Press.