Volume 7, Issue 2, June 2019, Page: 41-46
Effect of Magnesium Supplementation to Prevent Nephrotoxicity on the Antitumor Activity of Cisplatin
Megumi Yasuda, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
Shuichi Kishimoto, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
Rika Ebara, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
Manabu Amano, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Japan
Shoji Fukushima, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan
Received: Aug. 5, 2019;       Accepted: Aug. 24, 2019;       Published: Sep. 9, 2019
DOI: 10.11648/j.jctr.20190702.13      View  19      Downloads  10
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.
Cisplatin, Magnesium, Transporter, Accumulation
To cite this article
Megumi Yasuda, Shuichi Kishimoto, Rika Ebara, Manabu Amano, Shoji Fukushima, Effect of Magnesium Supplementation to Prevent Nephrotoxicity on the Antitumor Activity of Cisplatin, Journal of Cancer Treatment and Research. Vol. 7, No. 2, 2019, pp. 41-46. doi: 10.11648/j.jctr.20190702.13
Copyright © 2019 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cvitkovic E, Spaulding J, Bethune V, Martin J, Whitmore WF (1977) Improvement of cis-dichlorodiammineplatinum (NSC 119875): therapeutic index in an animal model. Cancer 39: 1357-1361.
Finley RS, Fortner CL, Grove WR (1985) Cisplatin nephrotoxicity: a summary of preventative interventions. Drug Intell Clin Pharm 19: 362-367.
Lajer H, Daugaard G (1999) Cisplatin and hypomagnesemia. Cancer Treat Rev 25: 47-58.
Lajer H, Kristensen M, Hansen HH, Nielsen S, Frøkiaer J, Ostergaard LF, Christensen S, Daugaard G, Jonassen TE (2005) Magnesium depletion enhances cisplatin-induced nephrotoxicity. Cancer Chemother Pharmacol 56: 535-542.
Tong GM, Rude RK (2005) Magnesium deficiency in critical illness. J Intensive Care Med 20: 3-17.
Hansen BA, Bruserud Ø (2018) Hypomagnesemia in critically ill patients. J Intensive Care 6: 21. https://doi.org/10.1186/s40560-018-0291-y.
Goren MP (2003) Cisplatin nephrotoxicity affects magnesium and calcium metabolism. Med Pediatr Oncol 41: 186-189.
van Angelen AA, Glaudemans B, van der Kemp AW, Hoenderop JG, Bindels RJ (2013) Cisplatin-induced injury of the renal distal convoluted tubule is associated with hypomagnesaemia in mice. Nephrol Dial Transplant 28: 879-889.
Okuda M, Tsuda K, Masaki K, Hashimoto Y, Inui K (1999) Cisplatin-induced toxicity in LLC-PK1 kidney epithelial cells: role of basolateral membrane transport. Toxicol Lett 106: 229-235.
Endo T, Kimura O, Sakata M (2000) Carrier-mediated uptake of cisplatin by the OK renal epithelial cell line. Toxicology 146: 187-195.
Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K (2007) Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol 74: 477-487.
Yokoo K, Murakami R, Matsuzaki T, Yoshitome K, Hamada A, Saito H (2009) Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats. Clin Exp Nephrol 13: 578-584.
Yonezawa A, Inui K (2011) Organic cation transporter OCT/SLC22A and H(+)/organic cation antiporter MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol 81: 563-568.
Bodnar L, Wcislo G, Gasowska-Bodnar A, Synowiec A, Szarlej-Wcisło K, Szczylik C (2008) Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: a randomised phase II study. Eur J Cancer 44: 2608-2614.
Yoshida T, Niho S, Toda M, Goto K, Yoh K, Umemura S, Matsumoto S, Ohmatsu H, Ohe Y (2014) Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: a retrospective study. Jpn J Clin Oncol 44: 346-354.
Saito Y, Okamoto K, Kobayashi M, Narumi K, Yamada T, Iseki K (2017) Magnesium attenuates cisplatin-induced nephrotoxicity by regulating the expression of renal transporters. Eur J Pharmacol 811: 191-198.
Filipski KK, Loos WJ, Verweij J, Sparreboom A (2008) Interaction of Cisplatin with the human organic cation transporter 2. Clin Cancer Res 14: 3875-3880.
Nakamura T, Yonezawa A, Hashimoto S, Katsura T, Inui K (2010) Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol 80: 1762-1767.
Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM (2008) The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol 48: 495-535.
Yang W, Lee JY, Nowotny M (2006) Making and breaking nucleic acids: two-Mg2+-ion catalysis and substrate specificity. Mol Cell 22: 5-13.
Matsumoto S, Tanaka T, Kurokawa H, Matsuno K, Hayashida Y, Takahashi T (2007) Effect of copper and role of the copper transporters ATP7A and CTR1 in intracellular accumulation of cisplatin. Anticancer Res 27: 2209-2216.
Akerfeldt MC, Tran CM, Shen C, Hambley TW, New EJ (2017) Interactions of cisplatin and the copper transporter CTR1 in human colon cancer cells. J Biol Inorg Chem 22: 765-774.
Sahni J, Scharenberg AM (2013) The SLC41 family of MgtE-like magnesium transporters. Mol Aspects Med 34: 620-628.
de Baaij JH, Arjona FJ, van den Brand M, Lavrijsen M, Lameris AL, Bindels RJ, Hoenderop JG (2016) Identification of SLC41A3 as a novel player in magnesium homeostasis. Sci Rep 6: 28565. https://doi.org/10.1038/srep28565.
Browse journals by subject