Fluvastatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood–testis barrier via mTOR signaling pathway

• Published in: Human & experimental toxicology 2019-12, Vol.38 (12), p.1329-1343
• Main Authors: Gurel, Cevik, Kuscu, Gokce Ceren, Buhur, Aylin, Dagdeviren, Melih, Oltulu, Fatih, Karabay Yavasoglu, Nefise Ulku, Yavasoglu, Altug
• Format: Article
• Language: English
• Subjects: Animals; Anthracycline; Antibiotics; Antibiotics, Antineoplastic - adverse effects; Antioxidants; Apoptosis; Biosynthesis; Blood; Blood-Testis Barrier - drug effects; Cholesterol; Coenzyme A; Connexin 43; Doxorubicin; Doxorubicin - adverse effects; Fluvastatin; Fluvastatin - therapeutic use; Free radicals; Germ cells; Hematology; Lipid peroxidation; Lipids; Male; Matrix metalloproteinase; Matrix metalloproteinases; Metalloproteinase; Model testing; Molecular modelling; Oxidative stress; Oxidative Stress - drug effects; Peroxidation; Polymerase chain reaction; Protective Agents - therapeutic use; Rapamycin; Rats, Sprague-Dawley; Reactive oxygen species; Signal transduction; Signal Transduction - drug effects; Solid tumors; Sperm Count; Superoxide; Testes; Testis - drug effects; Testis - metabolism; Testis - pathology; TOR protein; TOR Serine-Threonine Kinases - metabolism; Toxicity; Tumors
• ISSN: 0960-3271; 1477-0903
• DOI: 10.1177/0960327119862006

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.