Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity

Abstract

Approximately 30% of all cancer patients treated with cisplatin, a widely used broad-spectrum chemotherapeutic agent, experience acute kidney injury (AKI). Almost all patients receiving cisplatin have magnesium (Mg) losses, which are proposed to aggravate AKI. Currently, there are no methods to successfully treat or prevent cisplatin-AKI. Whereas Mg supplementation has been shown to reduce AKI in experimental models and several small clinical trials, the effects of Mg status on tumor outcomes in immunocompetent tumor-bearing mice and humans have not been investigated. The purpose of this study was to further examine the effects of Mg deficiency (±Mg supplementation) on cisplatin-mediated AKI and tumor killing in immunocompetent mice bearing CT26 colon tumors. Using a model where cisplatin alone (20 mg/kg cumulative dose) produced minimal kidney injury, Mg deficiency significantly worsened cisplatin-mediated AKI, as determined by biochemical markers (blood urea nitrogen and plasma creatinine) and histological renal changes, as well as markers of renal oxidative stress, inflammation, and apoptosis. By contrast, Mg supplementation blocked cisplatin-induced kidney injury. Using LLC-PK renal epithelial cells, we observed that Mg deficiency or inhibition of Mg uptake significantly enhanced cisplatin-induced cytotoxicity, whereas Mg supplementation protected against cytotoxicity. However, neither Mg deficiency nor inhibition of Mg uptake impaired cisplatin-mediated killing of CT26 tumor cells in vitro. Mg deficiency was associated with significantly larger CT26 tumors in BALB/c mice when compared with normal-fed control mice, and Mg deficiency significantly reduced cisplatin-mediated tumor killing in vivo. Finally, Mg supplementation did not compromise cisplatin's anti-tumor efficacy in vivo.

Hypomagnesemia and Survival in Patients with Ovarian Cancer Who Received Chemotherapy with Carboplatin

“…Hypomagnesemia and inhibition of renal magnesium uptake are observed to have an additive effect on cisplatininduced renal toxicity in animal models, whereas magnesium infusion significantly reduces renal cisplatin accumulation and cisplatin-induced nephrotoxicity in a dose-dependent manner [14,15]. In a study of mice bearing colon tumors, magnesium supplementation was shown to protect against cisplatin cytotoxicity without compromising cisplatin's antitumor efficacy in vivo [16]. Our study adds critical clinical evidence that appeals for research effort to study the impact of magnesium supplementation on survival in patients with ovarian cancer receiving platinum-based chemotherapy.…”

Hypomagnesemia in the Cancer Patient

“…66 , and preclinical studies have shown a protective effect of normal SMg levels in models of cisplatininduced nephrotoxicity. [67][68][69]…”

Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury

“…Cisplatin decreases serum magnesium [26]. Magnesium deficiency increases AKI severity [27] by decreasing expression of efflux transporters and allowing for cisplatin accumulation in tubular cells [28,29]. Kumar et al recently showed that magnesium supplementation protected against AKI and did not interfere with the anti-tumour effects of cisplatin [27].…”