Cisplatin is one of the most commonly used chemotherapeutic agents. In the US, there are more than 2000 ongoing clinical trials investigating cisplatin in patients with ovarian, testicular, bladder, cervical, and head/neck cancers, among others. Unfortunately, approximately 25-30% of patients receiving cisplatin suffer nephrotoxicity despite its potency as an anti-tumor agent. This is a challenge in the oncology clinical setting where either dose reductions or discontinuation of cisplatin are often required to salvage the kidneys leaving the patient and clinician with limited options given the efficacy and affordability of this drug. An important contributor to cisplatin-mediated nephrotoxicity is the accompanying electrolyte imbalances, including hypomagnesemia. Magnesium (Mg) is an essential dietary mineral required for normal body functioning and cellular processes. Surprisingly, Mg consumption (via foods and supplements) among most Americans, particularly the elderly, is below the recommended daily allowance. In addition, many medications and disease conditions reduce the availability of dietary Mg. Therefore, we sought to examine the effects of Mg deficiency and Mg supplementation following Mg deficiency on cisplatin-mediated acute kidney injury (AKI) using a mouse model. We observed that Mg deficiency exacerbates cisplatin-induced AKI, whereas correction of Mg status protects against cisplatin-mediated AKI. Additional studies detail the cellular and molecular mechanisms by which Mg provides renoprotection, namely by attenuating cisplatin-induced inflammation, oxidative stress and apoptosis. In addition, we show for the first time that Mg supplementation reduces the platinum accumulation in the kidneys possibly by affecting the efflux of cisplatin by the renal epithelial cells. While protecting the kidneys, Mg supplementation did not compromise cisplatin-induced cytotoxicity using several human cancer cell lines, suggesting the Mg does not interfere with the chemotherapeutic efficacy of cisplatin in vitro. The results of this study warrant future large scale clinical studies to better monitor patients’ Mg status prior to and during cisplatin treatment and to develop improved Mg supplementation protocols that provide nephroprotection without compromising cisplatin’s potent chemotherapeutic efficacy.
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Malvika Solanki, MD