THE ROLE OF P90 RIBOSOMAL S6 KINASE AND AUTOPHAGY IN SUNITINIB AND PONATINIB-INDUCED CARDIOTOXICITY
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In recent years, the paradigm cancer management has shifted towards a targeted approach. Among the newly targeted anticancer therapies are ponatinib and sunitinib, small molecules tyrosine kinase inhibitors (TKIs), used for various types of cancer. Despite their superb anticancer effects, their use has been associated with cardiovascular toxicities. Therefore, the present study aimed to investigate the cardiotoxic effects associated with ponatinib and sunitinib and to define the underlying cardiotoxic signaling pathways. In the current study, an in vitro rat cardiomyoblast (H9c2) model was used to assess the cardiotoxic effects of sunitinib and ponatinib following 6 and 24 hours. Cardiomyoblast loss was characterized by MTT assay and flow cytometer analyses. Cardiomyoblast hypertrophy was assessed by measuring H9c2 cell surface area and atrial natriuretic peptide (ANP) mRNA expression. The potential molecular mechanisms of cardiotoxicity was examined by measuring p90RSK phosphorylation and autophagic flux. Both ponatinib and sunitinib induced the highest cardiotoxic effects among the screened TKIs. Sunitinib and ponatinib treatment reduced H9c2 cardiomyoblast cell viability and induced apoptotic cell death. Sunitinib treatment induced cardiomyoblast hypertrophy, while ponatinib treatment caused cellular detachment and cellular shrinkage. In terms of molecular pathways, ponatinib treatment induced p90RSK phosphorylation and autophagy, while sunitinib treatment inhibited p90RSK activity and induced autophagy. Inhibition of p90RSK or autophagy using BID or CQ, respectively, was associated with further cellular death. Our study compared the cardiotoxicity of different clinically-approved TKIs and identified the potential mechanisms of cardiotoxicity. This study demonstrated for the first time the different cardiotoxic effects associated with ponatinib treatment in H9c2 cell line.
- Master in Pharmacy [28 items ]