The effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the nephrotoxicity in the mouse during repeated cisplatin (CDDP) treatments

Abstract

Previously, we reported that specific lower dose of sodium 2,3-dimercapto-1-propanesulfonic acid (DMPS) which is an antidote to heavy metal intoxication, inversely enhanced cisplatin (CDDP)-induced antitumor activity to S-180 cell-bearing mouse. This activity was only weak with meso-2,3-dimercaptosuccinic acid (DMSA), however. This study investigated the effects of lower doses of DMPS or DMSA on the nephrotoxicity and kinetics of CDDP. Kidney and blood isolated from female mice which received CDDP with or without DMPS or DMSA once daily for 4 days were provided for measuring levels of blood urea nitrogen (BUN) and transporter proteins (OCT2: organic cation transporter; MATE1: multidrug and toxin extrusion) mRNA, and CDDP-originated platinum, and TUNEL staining of renal tubular cells. DMPS or DMSA reduced effectively CDDP-induced BUN, and caused a moderate reduction of platinum in kidney. Additionally, both dimercapto-compounds restored the CDDP-reduced mRNA levels of transporter proteins (OCT2 and MATE1), and apparently suppressed the CDDP-induced apoptosis. These results suggest that DMPS, as well as DMSA, at approximate 17-fold dose (μmol/kg) of CDDP, has an enough potential to reverse the CDDP nephrotoxicity, and concomitant use of DMPS considering both dose and timing for administration is potentially useful for preventing nephrotoxicity and enhancing antitumor activity during CDDP chemotherapy.

1. Introduction

Cisplatin (cis-diammine-dichloroplatinum; CDDP), an inorganic platinum complex has been evaluated as a most available chemotherapeutic drug for various types of malignant tumors.1, 2, 3, 4 However, CDDP-induced nephrotoxicity is a major limitation to CDDP-based chemotherapy.5 The causes of the renal toxicity appeared to be due to the accumulation of CDDP in the kidneys followed by apoptosis of renal tubular cells.6 Apoptosis induced by CDDP seems to be based on mitochondria-dependent and -independent pathways,7 partly through the activation of caspase-3.8 Further, CDDP-generated oxidant stress also appears to contribute to the apoptosis of renal tubular cells.9 On the other hand, several reports offered an aspect that CDDP impaired the function of transporters on the renal tubular cell membranes to be resulted in renal cumulative uptake of CDDP.10, 11 Major transporters involved in the uptake and excretion of CDDP in the renal tubular cells are organic cation transporter (OCT) family and multi drug and toxin extrusion (MATE) family. In these transporters, OCT2 and MATE1 play significant roles in excretion of BUN or metabolites of drugs.12, 13, 14 The OCT family is driven electrogenetically by inside-negative membrane potentials, consequently taking diverse organic cations into renal tubular cells.15 In contrast, the MATE family, which mediates the exchange of organic cations with hydrogen ions in renal brush-border membranes, is suggested to be responsible for the final step of urinary excretion of cationic drugs including CDDP.16, 17

Dithiol metal chelators such as 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are generally considered suitable for treating cases of heavy metal poisoning, including those caused by lead,18 mercury,19, 20 cadmium,21, 22 and copper.23 In the previous report, we showed that DMPS, but not DMSA, synergistically enhanced the antitumor activity of CDDP with 1.4-fold efficacy, only when two drugs were administered at an adequate dose ratio and time interval.24 However, when DMPS enhanced the antitumor effects of CDDP, it is not clear how DMPS influenced to the nephrotoxicity. The present study, by means of examining the changes of BUN, kinetics of platinum, expression of cation transporter genes and apoptosis of renal tubular cells, investigated the ability of DMPS to protect renal tissue against CDDP-induced toxicity at lower doses which enhanced antitumor effect of CDDP, while comparing to the potency of DMSA.