Effect of Magnesium Supplementation to Prevent Nephrotoxicity on the Antitumor Activity of Cisplatin

Abstract

Background: Cisplatin (CDDP) is one of the most widely used anticancer drugs, but CDDP often leads to nephrotoxicity, which limits its clinical effectiveness. Magnesium (Mg) supplementation is recommended for the avoidance of CDDP-induced nephrotoxicity. However, there is a concern that exposing cancer cells to Mg may suppress the antitumor effect of CDDP. Methods: Transporter expression, intracellular platinum and Mg levels, and cytotoxicity of CDDP after Mg exposure were assessed in human hepatocellular carcinoma (HepG2) and human ovarian carcinoma (2008) cells. Results: In HepG2 cells, Mg exposure significantly increased mRNA levels of multidrug and toxin extrusion 1 (MATE1), which mediates the renal excretion of CDDP, but did not alter its protein levels, including those of organic cation transporter 1 (OCT1), which mediates CDDP uptake in renal tubular and cancer cells, and multidrug resistance-associated protein 2 (MRP2), which mediates CDDP efflux in cancer cells. In 2008 cells, MATE1 protein expression could not be detected, but a slight increase in MRP2 and OCT1 protein expression was observed after Mg exposure. Intracellular Mg levels were significantly increased due to Mg exposure in both cells. However, intracellular platinum levels and cytotoxicity of CDDP were not affected in both cells, even with 2 mM Mg co-exposure. Conclusion: This study found that Mg exposure only slightly changed transporter expression and did not affect intracellular platinum levels and CDDP cytotoxicity in HepG2 and 2008 cells. Thus, Mg supplementation can be used to avoid CDDP-induced renal toxicity without affecting the accumulation of CDDP in cancer cells and its cytotoxicity.