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

Toxins

Hitoshi Uchiyama²  Masayuki Tsujimoto⁴  Tadakazu Shinmoto⁴  Hitomi Ogino⁴  Tomoko Oda⁴  Takuya Yoshida⁴  Taku Furukubo¹  Satoshi Izumi¹  Tomoyuki Yamakawa³  Hidehisa Tachiki⁵  Tetsuya Minegaki⁴ 

[1] Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan;Pharmacovigilance and Post Marketing Surveillance Department, Towa Pharmaceutical Co. Ltd., 2-11, Shinbashi-cho, Kadoma, Osaka 571-8580, Japan;Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan;Department of Clinical Pharmacy, Faculty of Pharmaceutical Science, Kyoto Pharmaceutical University, 5 Misasagi nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan;Research and Development Division, Towa Pharmaceutical Co. Ltd., Kyoto Research Park KISTIC#202, 134, Chudoji Minami-Machi, Shimogyo-ku, Kyoto 600-8813, Japan

关键词: cytotoxicity;    statin;    uremic toxin;    end-stage renal failure;    rhabdomyolysis;   

DOI  :  10.3390/toxins6092612

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.