Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood-testis barrier via mTOR signaling pathway
Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood-testis barrier via mTOR signaling pathway
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DOI：
10.1177/0960327119862006
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发表时间：
2019-07-04
影响因子：
2.8
通讯作者：
Yavasoglu, Altug
中科院分区：
文献类型：
--
作者：
Gurel, Cevik;Kuscu, Gokce Ceren;Yavasoglu, Altug
多柔比星（DOX）是一种蒽环类抗生素衍生物，目前仍广泛用于实体瘤和血液系统恶性肿瘤的治疗。DOX的临床使用由于急性和慢性肾脏、心脏、血液学和睾丸毒性而受到很大限制。以往的研究表明，氧化应激、脂质过氧化和生殖细胞凋亡是DOX所致睾丸毒性的主要因素，但DOX所致睾丸损伤的分子机制尚未完全阐明。氟伐他汀是一种降胆固醇药物，通过抑制羟甲基戊二酰辅酶A（胆固醇生物合成的关键酶）发挥作用。氟伐他汀除具有降胆固醇作用外，还具有清除羟自由基和超氧自由基的抗氧化作用，通过作用于哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，对肥胖引起的睾丸损伤具有保护作用。本研究旨在通过组织化学、免疫组化、生化和实时聚合酶链反应分析来探讨氟伐他汀对DOX诱导的睾丸毒性模型可能的保护和治疗作用。本研究提示，氟伐他汀可能通过清除活性氧，调节mTOR、缝隙连接蛋白43、基质金属蛋白酶9蛋白和信使核糖核酸的表达，发挥保护和治疗作用，这些蛋白和信使核糖核酸在调节血睾屏障中起重要作用。另一方面，发现使用氟伐他汀作为保护/预防剂比使用该药物进行治疗更有效。根据这些信息，氟伐他汀可能是一种候选药物，可用于预防接受DOX治疗的男性中观察到的睾丸毒性。
Doxorubicin (DOX) is an anthracycline derivative antibiotic that still frequently used in the treatment of solid tumors and hematological malignancies. The clinical use of DOX is largely restricted due to acute and chronic renal, cardiac, hematological, and testicular toxicities. Previous studies have indicated that oxidative stress, lipid peroxidation, and apoptosis in germ cells are the main factors in DOX-induced testicular toxicity, but the entire molecular mechanisms that responsible for DOX-induced testicular damage are not yet fully understood. Fluvastatin is a cholesterol-lowering agent that acts by inhibiting hydroxylmethyl glutaryl coenzyme A, the key enzyme for cholesterol biosynthesis. In addition to its cholesterol-lowering effect, fluvastatin showed an antioxidant effect by cleaning hydroxyl and superoxide radicals and this drug could have a protective effect by acting on the mammalian target of rapamycin (mTOR) signal pathway in testicular damage caused by obesity. This study aimed to investigate the possible protective and therapeutic effects of fluvastatin on the DOX-induced testicular toxicity model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction analyses. The present study indicates that fluvastatin may have a protective and therapeutic effect by removing reactive oxygen species and by regulating the mTOR, connexin 43, and matrix metalloproteinase 9 protein and messenger ribonucleic acid expressions, which play an important role in regulating the blood-testis barrier. On the other hand, the use of fluvastatin as a protective/prophylactic agent was found to be more effective than the use of this drug for treatment. In light of this information, fluvastatin may be a candidate agent that can be used to prevent testicular toxicity observed in men receiving DOX treatment.