Abstract 2659: Cilastatin attenuates cisplatin-induced proximal tubular cell damage without compromising antitumoral activity

Abstract

Abstract Introduction: Cisplatin (CDDP) is a very effective and common treatment in solid malignancies. One of the most important side effects of CDDP is the nephrotoxicity. Nephrotoxicity is a limitating side effect on treatment with CDDP, preventing patients with limit kidney function of receiving the drug and stopping treatment once kidney function has worsened. Cilastatin (Cls) is a specific inhibitor of renal dedydrodipeptidase I (DHP-I) which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. In this work we hypothesized that Cls acts as a nephroprotector against CDDP-induced damage without compromising antitumor activity. Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different malignancies (colon, breast, ovarian, bladder) were cultured with different concentrations of CDDP (1, 10 and 30 μM) in the presence or absence of Cls. Cell viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Raft staining was measured with toxine B choleric and FasL by confocal microscopy. Results: Cls interfered with CDDP-induced FasL signalling at raft level on PTCs brush border. Concomitant treatment with Cls reduced CDDP-induced changes. Several tumoral cell lines were tested with CDDP and Cls together. Cls did not increase or decreased tumor growth alone or in combination with CDDP. CDDP sensitivity was not affected by Cls. Conclusion: By binding a DHP-I, Cls blocks CDDP-induced PTCs apoptosis but it does not affect the CDDP antitumoral activity. Our findings suggest that the affinity of Cls for renal DHP-I make this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Cls administration might represent a novel strategy in the prevention of CDDP-induced acute renal injury. Cls treatment could potentially increase the number of patients undergoing CDDP treatment or maintaining treatment. Further clinical trials for renal function preservation in cancer patients are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2659. doi:1538-7445.AM2012-2659