Extended regorafenib treatment can be linked with mitochondrial damage leading to cardiotoxicity.


Boran T., Akyildiz A., Jannuzzi A. T. , Alpertunga B.

Toxicology letters, vol.336, pp.39-49, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 336
  • Publication Date: 2021
  • Doi Number: 10.1016/j.toxlet.2020.11.003
  • Journal Name: Toxicology letters
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, Communication Abstracts, EMBASE, Environment Index, Food Science & Technology Abstracts, MEDLINE, Metadex, Veterinary Science Database, Civil Engineering Abstracts
  • Page Numbers: pp.39-49
  • Keywords: Regorafenib, Cardiotoxicity, Mitochondrial damage, Tyrosine kinase inhibitors, TYROSINE KINASE INHIBITORS, IN-VITRO, VENTRICULAR HYPERTROPHY, MECHANISMS, STRESS, HEART, EXPRESSION, FUSION, OPA1, DYSFUNCTION
  • Istanbul University Affiliated: Yes

Abstract

Regorafenib (RGF) has a great success in the treatment of colorectal cancer, gastrointestinal stromal tumours and hepatocellular carcinoma by inhibiting angiogenic, stromal and oncogenic kinases. However, RGF can induce life-threatening cardiotoxicity including hypertension and cardiac ischemia/infarction. The molecular mechanism of the adverse effects has not been elucidated. Mitochondrial dysfunction is one of the major causes of cardiac diseases since cardiac cells highly need ATP for their contractility. Therefore, we aimed to investigate molecular mechanisms of RGF-induced cardiac adverse effects using H9c2 cell model by focusing on mitochondria. Cells were treated with 0-20 mu M RGF for 48 and 72 h. According to our results, RGF inhibited cell proliferation and decreased the ATP content of the cells depending on the exposure time and concentration. Loss of mitochondrial membrane potential was also observed at high dose. Mitochondrial fusion/fission genes and antioxidant SOD2 (superoxide dismutase) gene expression levels increased at high doses in both treatments. Mitochondrial DNA content decreased as exposure time and concentration increased. Also, protein expression levels of mitochondrial complex I and V have reduced and stress protein HSP70 level has increased following RGF treatment. Structural abnormalities in mitochondria was seen with transmission electron microscopy at the applied higher doses. Our findings suggest that RGF-induced cardiotoxicity may be associated with mitochondrial damage in cardiac cells. (C) 2020 Elsevier B.V. All rights reserved.