Imatinib‑ and ponatinib‑mediated cardiotoxicity in zebrafish embryos and H9c2 cardiomyoblasts
Date
2024-04-26Author
ZAKARIA, ZAIN ZSULEIMAN, MUNA
BENSLIMANE, FATIHA M.
AL‑BADR, MASHAEL
SIVARAMAN, SIVARAMAN
KORASHY, HESHAM M
AHMAD, FAREED
UDDIN, SHAHAB
MRAICHE, FATIMA
YALCIN, HUSEYIN C
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Tyrosine kinase inhibitors (TKIs) offer targeted therapy for cancers but can cause severe cardiotoxicities. Determining their dose‑dependent impact on cardiac function is required to optimize therapy and minimize adverse effects. The dose‑dependent cardiotoxic effects of two TKIs, imatinib and ponatinib, were assessed in vitro using H9c2 cardiomyoblasts and in vivo using zebrafish embryos. In vitro, H9c2 cardiomyocyte viability, apoptosis, size, and surface area were evaluated to assess the impact on cellular health. In vivo, zebrafish embryos were analyzed for heart rate, blood flow velocity, and morphological malformations to determine functional and structural changes. Additionally, reverse transcription‑quantitative PCR (RT‑qPCR) was employed to measure the gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), established markers of cardiac injury. This comprehensive approach, utilizing both in vitro and in vivo models alongside functional and molecular analyses, provides a robust assessment of the potential cardiotoxic effects. TKI exposure decreased viability and surface area in H9c2 cells in a dose‑dependent manner. Similarly, zebrafish embryos exposed to TKIs exhibited dose‑dependent heart malformation. Both TKIs upregulated ANP and BNP expression, indicating heart injury. The present study demonstrated dose‑dependent cardiotoxic effects of imatinib and ponatinib in H9c2 cells and zebrafish models. These findings emphasize the importance of tailoring TKI dosage to minimize cardiac risks while maintaining therapeutic efficacy. Future research should explore the underlying mechanisms and potential mitigation strategies of TKI‑induced cardiotoxicities.
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