Mitochondrial dynamics imbalance and mitochondrial dysfunction contribute to the molecular cardiotoxic effects of lenvatinib
| Autor: | Ayse Tarbin Jannuzzi, Tuğçe Boran, Buket Alpertunga, Aysenur Gunaydin Akyildiz |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
FIS1 Cell Survival SOD2 MFN2 Antineoplastic Agents Mitochondrion Pharmacology Toxicology Cardiotoxins Mitochondrial Dynamics Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine MFN1 Animals Myocytes Cardiac Cardiotoxicity Dose-Response Relationship Drug Chemistry Phenylurea Compounds medicine.disease Mitochondria Rats Mitochondrial toxicity 030104 developmental biology 030220 oncology & carcinogenesis Quinolines Lenvatinib |
| Zdroj: | Toxicology and applied pharmacology. 423 |
| ISSN: | 1096-0333 |
| Popis: | Lenvatinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of resistant differentiated thyroid cancer, advanced renal cell carcinoma, unresectable hepatocellular carcinoma, and endometrial carcinoma. Although it is successful in cancer treatment, it can cause life-threatening side effects such as cardiotoxicity. The molecular mechanism of cardiotoxicity caused by lenvatinib is not fully known. In this study, the molecular mechanism of lenvatinib's cardiotoxicity was investigated focusing on mitochondrial toxicity in the H9c2 cardiomyoblastic cell line. Lenvatinib inhibited cell viability at 48 and 72 h exposure with three selected concentrations (1.25 μM, 5 μM and 10 μM); and inhibited intracellular ATP after 72 h exposure compared to the control group. Mitochondrial membrane potential was decreased after 48 h and did not show significant changes after 72 h exposure. Evaluated with real-time PCR, mitochondrial dynamics (Mfn1, Mfn2, OPA1, DRP1, Fis1) expression levels after lenvatinib treatment significantly changed. Lenvatinib triggered the tendency from fusion to fission in mitochondria after 48 h exposure, and increased both fusion and fission after 72 h. The mtDNA ratio increased after 48 h and decreased after 72 h. ASK1, JNK and AMPKα2 increased. UCP2 showed downregulation, SOD2 level showed upregulation and Cat levels decreased after drug treatment. Nrf1 and Nrf2 also changed concentration-dependently. Protein carbonyl levels increased significantly after lenvatinib treatments indicating oxidative stress. The protein levels of the electron transport chain complexes, LONP1, UCP2, and P21 showed significant differences after lenvatinib treatment. The outcome of our study is expected to be a contribution to the understanding of the molecular mechanisms of TKI-induced cardiotoxicity. |
| Databáze: | OpenAIRE |
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