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

Abstract

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-H)(PTA)Cl]PF (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.

Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

“… (A and B). As expected, and in line with previous results,49 cisplatin alone causes a marked reduction of slice viability in both organs. Instead, cage C0 was substantially not toxic even at the highest tested…”

“…Thus, as proof of concept, cage C0, alone or encapsulating cisplatin, was tested for its toxicity on healthy rat kidney and liver tissues ex vivo using the precision-cut tissue slices (PCTS) technique. [46][47][48][49][50] PCTS are thin (150-250 μm) slices of viable tissue. In this model, all cells remain in their natural environment maintaining the original cell-cell and cell-matrix contacts, which are absent in classical 2D cell cultures in vitro.…”

“…46-50 Recently, we have successfully used the PCTS method to study the toxic effects of experimental anticancer organometallic compounds, including aminoferrocene-containing prodrugs, ruthenium-based kinase inhibitors, as well as gold(I) carbenes and gold(III) cyclometalated cytotoxic agents. [46][47][48][49][50] Thus, the viability of the liver and kidney slices was determined by incubating the PCTS with different concentrations of cage C0, alone or encapsulating cisplatin (cage:cisplatin = 1:2), for 24 h and measuring the ATP/protein content (see SI for details). Cisplatin was also administered in the same range of concentrations for comparison.…”

Gold(III) Complexes for Antitumor Applications: An Overview

“…The major involvement of the organic cation transporters (OCTs) and the multidrug andt oxin extrusion protein (MATE) transporters into the uptake mechanismo f18 c could be ruled out. [53] The more rigid cyclometalated C^N ligand scaffold based on 2-phenylpyridine has also been explored to make anticancer organogold complexesw ithv arious ancillary ligands, including chloride, carboxylates, cyclobutanedicarboxylate, sulfur-containing ligandsa nd phenyld erivatives (complexes 20 and 21, Figure 7). These complexes demonstrated antiproliferative properties similart oc isplatin on human leukemia (MOLT-4) and mouse tumour (C2C12) cell lines, with the cyclobutanedicarboxylato complex being the most promising compound of that series.…”

DNA–affibody nanoparticle delivery system for cisplatin-based breast cancer chemotherapy

“…Candidate systems include liposomes, micelles, polymers, and inorganic nanoparticles. [9][10][11][12][13] These systems enhance the permeability of cisplatin and its retention aer deposition in tumor tissue. However, there are some obvious drawbacks, such as a lack of targeting, difficulty in releasing the drug, and unsatisfactory clinical outcomes.…”