Cisplatin nephrotoxicity

Abstract

Cisplatin remains a major antineoplastic drug for the treatment of solid tumors. Its chief dose-limiting side effect is nephrotoxicity, which evolves slowly and predictably after initial and repeated exposure. The kidney accumulates cisplatin to a higher degree than other organs perhaps via mediated transport. Functionally, reduced renal perfusion and a concentrating defect characterize its nephrotoxicity, whereas morphologically necrosis of the terminal portion of the proximal tubule and apoptosis predominantly in the distal nephron characterize its effects on cell fate. Among the earliest reactions of the kidney to cisplatin is the activation of the MAPK cascade and molecular responses typical of the stress response. Repression of genes characteristic of the mature phenotype of the kidney, especially those serving transport function of the kidney, is also prominent. Metabolic responses, cell cycle events and the inflammatory cascade seem to be important determinants of the degree of renal failure induced by cisplatin. Manipulation of these responses may be exploited to reduce its toxicity clinically.

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK1 Cells

“…The binding of cisplatin to proteins in the cytosol may be non-enzymatic. When cisplatin enters the cell, the low intracellular chloride concentration can lead to the dissociation of one or more of the chlorides resulting in the formation of monoaquo and diaquo complexes, cis-[Pt(NH 3 ) 2 2+ . Platinum forms a co-ordinate covalent bond with negatively charged molecules such as the sulfur on cysteine.…”

“…Unfortunately, the drug cannot be administered at high doses due to its toxicity to renal proximal tubules and its neurotoxicity (2,3). Studies from many laboratories have implicated DNA damage as the primary mechanism by which cisplatin kills tumor cells and other dividing cells (4,5).…”

Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis

“…Nephrotoxicity is a major side effect of cisplatin (Arany and Safirstein, 2003), one of the most effective chemotherapy drugs for cancer (Niedner et al, 2001;Fuertesa et al, 2003;Siddik, 2003). In the kidneys, renal tubular cells are particularly sensitive to cisplatin injury.…”

“…Depending on its concentration, cisplatin induces necrosis as well as apoptosis in these cells, leading to acute renal failure. Multiple signaling pathways are activated by cisplatin in renal tubular cells (Baliga et al, 1998;Megyesi et al, 1998;Shiraishi et al, 2000;Kaushal et al, 2001;Nowak, 2002;Park et al, 2002;Ramesh and Reeves, 2002;Liu and Baliga, 2003;Tsuruya et al, 2003;Arany et al, 2004;Li et al, 2004;Sheikh-Hamad et al, 2004;Yu et al, 2005); however, it is unclear how these signals are integrated to determine cell injury and death (Arany and Safirstein, 2003).…”

Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity

“…1,2 Cisplatin preferentially accumulates in the kidney and induces damage to the kidney primarily in the S3 segment of proximal tubules with some damage to distal nephrons. 1,2 Although several targets of cisplatin in cells have been characterized, the primary biological target is generally considered to be DNA. 3 Cisplatin causes DNA damage due to its ability to form a platinum-DNA complex.…”