Kaushal Gur P, Kaushal Varsha, Herzog Christian, Yang Cheng
Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Department of Medicine, Little Rock, Arkansas 72205, USA.
Autophagy. 2008 Jul;4(5):710-2. doi: 10.4161/auto.6309. Epub 2008 May 20.
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.
顺铂化疗的主要副作用之一是中毒性急性肾损伤,这是由于顺铂在肾近端小管上皮细胞中优先蓄积并随后损伤这些细胞所致。凋亡是顺铂诱导肾小管细胞死亡的主要机制。我们最近还证明,自噬诱导是肾小管上皮细胞暴露于顺铂后的即时反应。抑制顺铂诱导的自噬可阻断自噬体的形成,并增强顺铂诱导的半胱天冬酶-3、-6和-7的激活、核碎裂和凋亡。自噬抑制剂使自噬转变为凋亡,这表明自噬诱导是肾小管细胞暴露于顺铂时观察到的凋亡前延迟期的原因。我们的研究提供了证据,表明顺铂诱导的自噬引发了一种抑制和延迟凋亡的适应性反应。自噬的有益作用在最小化或预防顺铂肾毒性方面具有潜在的临床意义。