On the toxicity and transport mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent

• Published in: Metallomics 2017-12, Vol.9 (12), p.1786-1795
• Main Authors: Spreckelmeyer, Sarah, Estrada-Ortiz, Natalia, Prins, Gerian G. H, van der Zee, Margot, Gammelgaard, Bente, Stürup, Stefan, de Graaf, Inge A. M, Groothuis, Geny M. M, Casini, Angela
• Format: Article
• Language: English
• Subjects: Accumulation; Adenosine Triphosphate - metabolism; Animals; Anticancer properties; Antineoplastic Agents - toxicity; Antiporters - metabolism; Cancer; Cimetidine; Cisplatin; Cisplatin - toxicity; Cytotoxicity; Cytotoxins - toxicity; Distal tubules; Excretion; Gene expression; Gold; Gold - toxicity; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Male; Metal compounds; Metals; Oct-2 protein; Organic Cation Transport Proteins - metabolism; Organic Cation Transporter 2 - metabolism; p53 Protein; Platinum; Proximal tubules; Rats; Rats, Wistar; Temperature effects; Tissues; Toxicity; Transport; Viability
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/c7mt00271h

Mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated. Here, we studied the toxic effects and accumulation mechanisms of cisplatin in healthy rat kidneys ex vivo , using the Precision Cut Tissue Slices (PCTS) method. In addition, for the first time, we investigated the nephrotoxic effects of an experimental anticancer cyclometallated complex [Au(py b -H)(PTA)Cl]PF 6 (PTA = 1,3,5-triazaphosphaadamantane). The viability of the kidney slices after metallodrug treatment was evaluated by ATP content determination and histomorphology analysis. A concentration dependent decrease in viability of PCKS was observed after exposure to cisplatin or the Au( iii ) complex, which correlated with the increase in slice content of Pt and Au, respectively. Metal accumulation in kidney slices was analysed by ICP-MS. The involvement of OCTs and MATE transporters in the accumulation of both metal compounds in kidneys was evaluated co-incubating the tissues with cimitedine, inhibitor of OCT and MATE. Studies of mRNA expression of the markers KIM-1, villin, p53 and Bax showed that cisplatin damages proximal tubules, whereas the Au( iii ) complex preferentially affects the distal tubules. However, no effect of cimetidine on the toxicity or accumulation of cisplatin and the Au( iii ) complex was observed. The effect of temperature on metallodrug accumulation in kidneys suggests the involvement of a carrier-mediated uptake process, other than OCT2, for cisplatin; while carrier-mediated excretion was suggested in the cases of the Au( iii ) complex. The toxic effects and accumulation mechanisms of cisplatin in healthy rat kidneys has been studied ex vivo , using the Precision Cut Tissue Slices (PCTS) method, in comparison to those exerted by an experimental cytotoxic Au( iii ) compound.