Dasatinib induces gene expression of CYP1A1, CYP1B1, and cardiac hypertrophy markers (BNP, β-MHC) in rat cardiomyocyte H9c2 cells

• Published in: Toxicology mechanisms and methods 2018-11, Vol.28 (9), p.678-684
• Main Author: Alsaad, Abdulaziz M. S.
• Format: Article
• Language: English
• Subjects: AhR; Animals; Antineoplastic Agents - toxicity; Biomarkers - analysis; BNP; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiotoxicity; Cell Culture Techniques; Cell Line; Cell Survival - drug effects; CYP1A1; CYP1B1; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1B1 - genetics; Dasatinib; Dasatinib - toxicity; Gene Expression - drug effects; H9c2; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Myosin Heavy Chains - genetics; Natriuretic Peptide, Brain - genetics; Rats; β-MHC
• ISSN: 1537-6516; 1537-6524
• DOI: 10.1080/15376516.2018.1497746

Dasatinib is a new selective tyrosine kinase inhibitor that targets certain kinases involved in cellular growth and development. This drug belongs to a novel anticancer therapy aiming to increase the survival in patients with imatinib-resistant mutations. However, the dasatinib toxicity was reported as a side effect leading to arrhythmias and/or heart failure. Here, we investigated the possibility of dasatinib-induced toxicity in rat cardiomyocyte H9c2 cells. Our objectives were to investigate the ability of dasatinib to induce expression of cytochrome P450 (CYP1A1, CYP1B1) and cardiac hypertrophy markers (BNP, β-MHC) genes in H9c2 cells. To test this hypothesis, H9c2 cells were incubated with dasatinib at two concentrations (20 and 40 μM). Thereafter, CYP1A1, CYP1B1, BNP, and β-MHC were determined at gene expression level. Our findings showed that dasatinib induces the CYP1A1, CYP1B1, BNP, and β-MHC mRNA. The involvement of AhR/CYP1A1 pathway in dasatinib toxicity was tested by resveratrol (RES), an AhR antagonist. Interestingly, the increase in mRNA of different genes by dasatinib was not affected by RES, which confirms that these effects are not mediated through AhR. In addition, this was accompanied by a significant inhibition of constitutive expression of these genes by RES. The current work provides the first evidence for the ability of dasatinib to induce hypertrophic markers in H9c2 cells through AhR-independent pathway.