title: Magnesium protects against cisplatin-induced acute kidney injury without compromising cisplatin-mediated killing of an ovarian tumor xenograft in mice.
abstract: Cisplatin, a commonly used chemotherapeutic for ovarian and other cancers, leads to hypomagnesemia in most patients and causes acute kidney injury (AKI) in 25-30% of patients. Previously, we showed that magnesium deficiency worsens cisplatin-induced AKI and magnesium replacement during cisplatin treatment protects against cisplatin-mediated AKI in non-tumor-bearing mice (Solanki MH, Chatterjee PK, Gupta M, Xue X, Plagov A, Metz MH, Mintz R, Singhal PC, Metz CN. Am J Physiol Renal Physiol 307: F369-F384, 2014). This study investigates the role of magnesium in cisplatin-induced AKI using a human ovarian tumor (A2780) xenograft model in mice and the effect of magnesium status on tumor growth and the chemotherapeutic efficacy of cisplatin in vivo. Tumor progression was unaffected by magnesium status in saline-treated mice. Cisplatin treatment reduced tumor growth in all mice, irrespective of magnesium status. In fact, cisplatin-treated magnesium-supplemented mice had reduced tumor growth after 3 wk compared with cisplatin-treated controls. While magnesium status did not interfere with tumor killing by cisplatin, it significantly affected renal function following cisplatin. Cisplatin-induced AKI was enhanced by magnesium deficiency, as evidenced by increased blood urea nitrogen, creatinine, and other markers of renal damage. This was accompanied by reduced renal mRNA expression of the cisplatin efflux transporter Abcc6. These effects were significantly reversed by magnesium replacement. On the contrary, magnesium status did not affect the mRNA expression of cisplatin uptake or efflux transporters by the tumors in vivo. Finally, magnesium deficiency enhanced platinum accumulation in the kidneys and renal epithelial cells, but not in the A2780 tumor cells. These findings demonstrate the renoprotective role of magnesium during cisplatin AKI, without compromising the chemotherapeutic efficacy of cisplatin in an ovarian tumor-bearing mouse model.
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York;
authors.forename: Malvika H
authors.initials: MH
authors.lastname: Solanki
authors.affiliation: Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York;
authors.forename: Prodyot K
authors.initials: PK
authors.lastname: Chatterjee
authors.affiliation: Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York;
authors.forename: Xiangying
authors.initials: X
authors.lastname: Xue
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York;
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts;
authors.forename: Ivy
authors.initials: I
authors.lastname: Rosales
authors.affiliation: Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Yeboah
authors.affiliation: Biostatistics Unit, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York.
authors.forename: Nina
authors.initials: N
authors.lastname: Kohn
authors.affiliation: Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Center for Immunology and Inflammation, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; Hofstra North Shore-LIJ School of Medicine, Manhasset, New York; cmetz@nshs.edu.
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002277:Carcinoma / Q000188:drug therapy; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects*; D019587:Dietary Supplements; D005260:Female; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008274:Magnesium / Q000627:therapeutic use*; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010984:Platinum / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D010984:Platinum; D008274:Magnesium; D002945:Cisplatin
keywords: hypomagnesemia; nephrotoxicity; renal protection