Possible involvement of oxidative stress in cisplatin-induced apoptosis in LLC-PK1 cells.
Use of cisplatin, a chemotherapeutic agent, is associated with toxicity as a significant number of patients develop a decline in renal function. The mechanisms by which cisplatin produces renal injury are not well understood. It has been suggested that free radical-catalyzed lipid peroxidation can induce apoptosis or necrosis leading to renal injury. This study examined whether low concentrations of cisplatin induce apoptosis in LLC-PK1 cells and whether caspases 1, 2, 3, 8, and 9 are activated during this event. Our results show a dose- and time-dependent induction of apoptosis by micromolar concentrations of cisplatin. Expression of oncogenes c-myc and p53 was induced, and except for caspase 1, all the other caspases tested were activated. Z-VAD, the broad-spectrum inhibitor of caspases, prevented caspase activation and apoptosis, but not c-myc and p53 induction. On the other hand, N-acetylcysteine prevented cisplatin-induced apoptosis as well as c-myc induction but not p53 induction. The antioxidant trolox also prevented cisplatin-induced apoptosis. The results suggest that antioxidants and caspase inhibitors may alleviate cisplatin-associated nephrotoxicity.
Xiao
T
T
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, 6.642 Basic Science Bldg., Galveston, TX 77555-0647, USA.
Choudhary
S
S
Zhang
W
W
Ansari
N H
NH
Salahudeen
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000494:pharmacology; D018929:Cell Culture Techniques; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000166:cytology; D015227:Lipid Peroxidation; D009336:Necrosis; D018384:Oxidative Stress; D013552:Swine
D000970:Antineoplastic Agents; D000975:Antioxidants; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020169:Caspases; D002945:Cisplatin