Aspirin reduces Ponatinib-induced cardiovascular toxic phenotypes and death in zebrafish

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Biomedicine & Pharmacotherapy Pub Date : 2024-10-01 DOI:10.1016/j.biopha.2024.117503

Ruiqi Yu , Nana Ai , Chen Huang , Danni Wang , Chao Bian , Wei Ge , Cheong-Meng Chong

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Abstract

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.

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阿司匹林可减少 Ponatinib 诱导的斑马鱼心血管毒性表型和死亡。

背景介绍泊纳替尼（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耐药的费城染色体阳性急性淋巴细胞白血病（Ph+ ALL）和慢性粒细胞白血病（CML）患者。然而，泊纳替尼引起的心血管不良事件是影响患者生存率的一个严重问题。因此，有必要寻找候选药物来降低泊纳替尼的心血管毒性。目的：研究阿司匹林对泊纳替尼诱导的斑马鱼心血管毒性的影响：方法：使用AB株野生型斑马鱼（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、血流量、心脏形态和功能。血栓的形成用 O-二联苯胺染色法检测。用RNA测序法评估了接受泊纳替尼治疗的斑马鱼幼体的转录组：结果：泊纳替尼不仅会降低存活率，还会导致心血管毒性事件，如心包水肿、心脏结构异常、低心率和血栓形成。此外，全身转录组分析表明，泊纳替尼会上调环氧化酶-1（COX-1）的表达。与其他抗血栓药物相比，COX-1抑制剂阿司匹林能更有效地减少泊纳替尼诱导的心血管毒性事件，并提高斑马鱼幼体的存活率：我们的研究结果表明，阿司匹林具有降低泊纳替尼诱导的心血管毒性的潜力。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.