TY - JOUR
T1 - Lazaroid compounds prevent early but not late stages of oxidant-induced cell injury
T2 - Potential explanation for the lack of efficacy of lazaroids in clinical trials
AU - Huang, Hong
AU - Patel, Prakash B.
AU - Salahudeen, Abdulla K.
N1 - Funding Information:
This work was supported by grants from the Kidney Care Foundation Inc. and NIEHS (ES 09264-01). Lazaroid compounds were provided as gifts from the Upjohn Company (Upjohn, Kalamazoo, MI).
PY - 2001
Y1 - 2001
N2 - Earlier in vitro studies demonstrated the remarkable potency of the lazaroid compounds to prevent oxidant-induced early cell injury. However, the ability of lazaroid compounds to limit oxidative injury in vivo (including renal ischemia-reperfusion) has been less certain, and the early clinical trials using lazaroids to limit CNS injury or organ injury in the setting of transplantation have not been promising. Lazaroid compounds are potent inhibitors of lipid peroxidation, and their inability to influence other key injury processes, particularly during the late stages of cell injury, might partly explain the limited clinical efficacy. To test this, renal tubular (LLC-PK1) cells were incubated with 250 μM 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 chelator 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 injury. In the early stage, 2-MAC suppressed H2O2-induced lipid peroxidation and LDH release, but not the DNA damage, ATP depletion or loss of cell replication. In contrast, DFO suppressed all of the measurements. In the late stages, despite continued suppression of lipid peroxidation, only DFO maintained significant cytoprotection against H2O2, and this was accompanied by reduced DNA damage, higher ATP levels and preservation of cell proliferation. Thus, the inability of the lazaroid compound 2-MAC to sustain cytoprotection in the later stages of cell injury might provide at least a partial explanation for the inefficiency of lazaroids to limit tissue injury in clinical and certain in vivo settings.
AB - Earlier in vitro studies demonstrated the remarkable potency of the lazaroid compounds to prevent oxidant-induced early cell injury. However, the ability of lazaroid compounds to limit oxidative injury in vivo (including renal ischemia-reperfusion) has been less certain, and the early clinical trials using lazaroids to limit CNS injury or organ injury in the setting of transplantation have not been promising. Lazaroid compounds are potent inhibitors of lipid peroxidation, and their inability to influence other key injury processes, particularly during the late stages of cell injury, might partly explain the limited clinical efficacy. To test this, renal tubular (LLC-PK1) cells were incubated with 250 μM 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 chelator 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 injury. In the early stage, 2-MAC suppressed H2O2-induced lipid peroxidation and LDH release, but not the DNA damage, ATP depletion or loss of cell replication. In contrast, DFO suppressed all of the measurements. In the late stages, despite continued suppression of lipid peroxidation, only DFO maintained significant cytoprotection against H2O2, and this was accompanied by reduced DNA damage, higher ATP levels and preservation of cell proliferation. Thus, the inability of the lazaroid compound 2-MAC to sustain cytoprotection in the later stages of cell injury might provide at least a partial explanation for the inefficiency of lazaroids to limit tissue injury in clinical and certain in vivo settings.
KW - Free radicals
KW - Lazaroids
KW - Lipid peroxidation
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U2 - 10.1006/phrs.2000.0740
DO - 10.1006/phrs.2000.0740
M3 - Article
C2 - 11207066
AN - SCOPUS:0034978941
SN - 1043-6618
VL - 43
SP - 55
EP - 61
JO - Pharmacological Research
JF - Pharmacological Research
IS - 1
ER -