State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 999078, China.
Department of Biomedical Sciences and Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.
Biomed Pharmacother. 2024 Nov;180:117503. doi: 10.1016/j.biopha.2024.117503. Epub 2024 Oct 1.
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.
To investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish.
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.
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.
Our findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.
波那替尼（Iclusig）是一种口服酪氨酸激酶 BCR-ABL 抑制剂，用于治疗对其他酪氨酸激酶抑制剂治疗耐药的费城染色体阳性急性淋巴细胞白血病（Ph ALL）和慢性髓性白血病（CML）患者。然而，波那替尼引起的不良心血管事件是一个严重的问题，影响患者的生存率。因此，有必要寻找候选药物来降低波那替尼的心血管毒性。
研究阿司匹林对斑马鱼中波那替尼诱导的心血管毒性的影响。
使用 AB 品系野生型斑马鱼（Danio rerio）、Tg（cmlc2: GFP）转基因斑马鱼和 Tg（gata1: dsRed）转基因斑马鱼作为体内模型，评估存活率、血流、心脏形态和功能。使用 O-二茴香胺染色检测血栓形成。使用 RNA 测序评估 Ponatinib 处理的斑马鱼幼虫的转录组。
波那替尼不仅降低了存活率，还导致了心血管毒性事件，如心包水肿、心脏结构异常、心率降低和血栓形成。此外，全基因组转录组分析表明，波那替尼上调了环氧化酶-1（COX-1）的表达。与其他抗血栓药物相比，COX-1 抑制剂阿司匹林更有效地降低了 ponatinib 诱导的心血管毒性事件，并提高了斑马鱼幼虫的存活率。
我们的研究结果表明，阿司匹林具有降低波那替尼诱导的心血管毒性的潜力。
