Fluvastatin alleviates doxorubicin-induced cardiac and renal toxicity in rats via regulation of oxidative stress, inflammation, and apoptosis associated genes expressions

Abstract

Doxorubicin (DOXO) is a cytostatic agent used in the chemotherapy protocol of several cancers for more than 40 years, but usage of this drug in cancer treatment has been limited due to severe renal and cardiac tissue toxicities that may result in death in patients. Fluvastatin (FV) is a fully synthetic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor used as a cholesterol-lowering agent in patients with hypercholesterolemia. Previous studies revealed that FV also exhibits antioxidant, anti-inflammatory, and antitumor activity. Additionally, our previous study indicated that FV exerts a prophylactic effect on DOXO-induced testicular toxicity by preventing lipid peroxidation, supporting the antioxidant system, and regulating the blood-testis barrier-associated genes expression. Herein, we purposed to evaluate the possible therapeutic and the protective effects of FV on the DOXO-induced cardiac and renal toxicitiy model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction (real-time PCR) analyses. Results point out protective use of FV exerts a beneficial effect by repressing lipid peroxidation and by regulating the inducible nitric oxide synthase (iNOS), nitric oxide synthase endothelial (eNOS), nuclear factor kappa-B (NF-κB), and Caspase-3 (Casp3) protein and mRNA expressions, which play an important role in mediating DOXO-induced renal and cardiac toxicity mechanisms. In conclusion, FV may be a candidate agent for the prevention of renal and cardiac toxicities in cancer patients receiving DOXO chemotherapy.

Keywords:

• Apoptosis
• cardiac toxicity
• doxorubicin
• fluvastatin
• inflammation
• renal toxicity

Acknowledgements

The experimental procedures on the animals in this study were performed at Ege University, Drug Research and Development and Pharmacokinetic Applications (ARGEFAR).

Disclosure statement

The authors declared no real, perceived or potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author contributions

FO and AY designed the research. ÇG, GCK, and AB performed animal experiments and histopathological and immunohistochemical staining. NÜKY performed and evaluated real-time PCR analysis. FO, AY, TK, and NÜKY analyzed and interpreted the data. ÇG and GCK wrote the manuscript. All authors reviewed the manuscript.

Additional information

Funding

This study was supported by the Ege University Scientific Research Projects Coordination Unit [grant number 18-TIP-016 (to FO)].