Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats

Abstract

Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.

Ameliorative potential of gemfibrozil and silymarin on experimentally induced nephrotoxicity in rats

“…However, cisplatin-induced nephrotoxicity is one of the most common side effects. More than 25% of patients develop acute nephrotoxicity after receiving cisplatin due to its accumulation within the proximal tubular cells of the kidney [6,29,30]. Several factors including inflammation, toxic damage and cell cycle arrest had been incriminated in the pathogenesis of cisplatin nephrotoxicity [31].…”

“…The mechanisms of cisplatin nephrotoxicity are still not fully understood. The nephrotoxicity of cisplatin seems to be due to cell membrane peroxidation, mitochondrial dysfunction, inhibition of protein synthesis, DNA damage, changes in the pro-apoptotic Bax protein and inhibition of the antioxidant system by pro-oxidant damage to the renal tissue [5,6]. Previous reports have demonstrated protective roles for antioxidants and free radical scavengers such as vitamin E, lipoic acid and N-acetylcysteine in cisplatin-induced acute nephrotoxicity [7].…”

Epidermal Growth Factor Receptor Inhibition with Erlotinib Partially Prevents Cisplatin-Induced Nephrotoxicity in Rats

“…Members of the Bcl-2 family, including pro-apoptotic proteins such as Bax and anti-apoptotic proteins such as Bcl-2, have been implicated as central regulators of mitochondrial permeability and caspase activation [29]. The ratio of Bax to Bcl-2 has been proposed as an index of the susceptibility of cells to apoptosis, such that an increased ratio indicates predisposition to apoptosis [30]. In the present study, the number of caspase-3-positive cells was significantly attenuated by erlotinib treatment in CP-N rats.…”

“…Lastly, the influence of erlotinib on antitumorigenic effects of CP was not proved. Further studies to evaluate whether the reduction of CP-elicited cell death by erlotinib was specific for the kidney by using different tumor cell lines like previous studies [30], [46] are needed.…”

Translational value of animal models of kidney failure

“…Another approach that may be close to clinical use is cilastatin. Cilastatin, which is now used to increase the half-life of beta-lactam antibiotics, protected rats from cisplatin nephrotoxicity (Humanes et al, 2012).…”