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Toxins 2014, 6(9), 2612-2625; doi:10.3390/toxins6092612

Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells

1
Pharmacovigilance and Post Marketing Surveillance Department, Towa Pharmaceutical Co. Ltd., 2-11, Shinbashi-cho, Kadoma, Osaka 571-8580, Japan
2
Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan
3
Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan
4
Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan
5
Research and Development Division, Towa Pharmaceutical Co. Ltd., Kyoto Research Park KISTIC#202, 134, Chudoji Minami-Machi, Shimogyo-ku, Kyoto 600-8813, Japan
*
Author to whom correspondence should be addressed.
Received: 2 June 2014 / Revised: 29 August 2014 / Accepted: 29 August 2014 / Published: 3 September 2014
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Abstract

The risk of myopathy and rhabdomyolysis is considerably increased in statin users with end-stage renal failure (ESRF). Uremic toxins, which accumulate in patients with ESRF, exert cytotoxic effects that are mediated by various mechanisms. Therefore, accumulation of uremic toxins might increase statin-induced cytotoxicity. The purpose of this study was to determine the effect of four uremic toxins—hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate, indole-3-acetic acid, and 3-indoxyl sulfate—on statin-induced myopathy. Differentiated rhabdomyosarcoma cells were pre-treated with the uremic toxins for seven days, and then the cells were treated with pravastatin or simvastatin. Cell viability and apoptosis were assessed by viability assays and flow cytometry. Pre-treatment with uremic toxins increased statin- but not cisplatin-induced cytotoxicity (p < 0.05 vs. untreated). In addition, the pre-treatment increased statin-induced apoptosis, which is one of the cytotoxic factors (p < 0.05 vs. untreated). However, mevalonate, farnesol, and geranylgeraniol reversed the effects of uremic toxins and lowered statin-induced cytotoxicity (p < 0.05 vs. untreated). These results demonstrate that uremic toxins enhance statin-induced apoptosis and cytotoxicity. The mechanism underlying this effect might be associated with small G-protein geranylgeranylation. In conclusion, the increased severity of statin-induced rhabdomyolysis in patients with ESRF is likely due to the accumulation of uremic toxins. View Full-Text
Keywords: cytotoxicity; statin; uremic toxin; end-stage renal failure; rhabdomyolysis cytotoxicity; statin; uremic toxin; end-stage renal failure; rhabdomyolysis
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Uchiyama, H.; Tsujimoto, M.; Shinmoto, T.; Ogino, H.; Oda, T.; Yoshida, T.; Furukubo, T.; Izumi, S.; Yamakawa, T.; Tachiki, H.; Minegaki, T.; Nishiguchi, K. Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells. Toxins 2014, 6, 2612-2625.

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