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

• Published in: Toxicology letters 2021-01, Vol.336, p.39-49
• Main Authors: Boran, Tugce, Akyildiz, Aysenur Gunaydin, Jannuzzi, Ayse Tarbin, Alpertunga, Buket
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Antineoplastic Agents - toxicity; Cardiotoxicity; Cell Line; Cell Proliferation - drug effects; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Dose-Response Relationship, Drug; Heart Diseases - chemically induced; Heart Diseases - genetics; Heart Diseases - metabolism; Heart Diseases - pathology; HSP70 Heat-Shock Proteins - metabolism; Membrane Potential, Mitochondrial - drug effects; Mitochondria, Heart - drug effects; Mitochondria, Heart - genetics; Mitochondria, Heart - metabolism; Mitochondria, Heart - pathology; Mitochondrial damage; Mitochondrial Dynamics - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phenylurea Compounds - toxicity; Pyridines - toxicity; Rats; Regorafenib; Time Factors; Tyrosine kinase inhibitors
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2020.11.003

•Regorafenib (RGF) inhibited cell proliferation and reduced ATP content of cells.•RGF disrupted mitochondrial membrane potential and mitochondrial structure.•High concentration of RGF up-regulated fission and fusion gene expressions.•RGF reduced mitochondrial complex I and V expressions and decreased mtDNA content.•HSP70 protein expression increased following high doses of RGF treatment. 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 μM 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.