Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity.
One of the major side effects of cisplatin chemotherapy is toxic acute kidney injury due to preferential accumulation of cisplatin in renal proximal tubule epithelial cells and the subsequent injury to these cells. Apoptosis is known as a major mechanism of cisplatin-induced cell death in renal tubular cells. We have also recently demonstrated that autophagy induction is an immediate response of renal tubular epithelial cell exposure to cisplatin. Inhibition of cisplatin-induced autophagy blocks the formation of autophagosomes and enhances cisplatin-induced caspase-3, -6, and -7 activation, nuclear fragmentation and apoptosis. The switch from autophagy to apoptosis by autophagic inhibitors suggests that autophagy induction was responsible for a pre-apoptotic lag phase observed on exposure of renal tubular cells to cisplatin. Our studies provide evidence that autophagy induction in response to cisplatin mounts an adaptive response that suppresses and delays apoptosis. The beneficial effect of autophagy has a potential clinical significance in minimizing or preventing cisplatin nephrotoxicity.
Kaushal
Gur P
GP
Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Department of Medicine, Little Rock, Arkansas 72205, USA. kaushalgurp@uams.edu
Kaushal
Varsha
V
Herzog
Christian
C
Yang
Cheng
C
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002945:Cisplatin / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology*; D013997:Time Factors
D000970:Antineoplastic Agents; D002945:Cisplatin