Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2024
Aspirin reduces Ponatinib-induced cardiovascular toxic phenotypes and death in zebrafish.
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Yu Ruiqi, Ai Nana, Huang Chen, Wang Danni, Bian Chao, Ge Wei, Chong Cheong-Meng
Аннотация
BACKGROUND: Ponatinib (Iclusig) is an oral tyrosine kinase BCR-ABL inhibitor for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) who are resistant to the therapies with other tyrosine kinase inhibitors. However, adverse cardiovascular events caused by Ponatinib are a serious issue that affects patients' survival rates. Thus, it is necessary to search for candidate drugs to reduce the cardiovascular toxicity of Ponatinib.
PURPOSE: To investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish.
METHODS: AB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing.
RESULTS: Ponatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae.
CONCLUSION: Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.
PURPOSE: To investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish.
METHODS: AB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing.
RESULTS: Ponatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae.
CONCLUSION: Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.