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Updated: Aug 25, 2025
Rapid Evaluation of Toxicity of Chemical Compounds Using Zebrafish Embryos
Published on: August 25, 2019
Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish
Huan-Chau Lin1,2, Ferry Saputra3,4, Gilbert Audira3,4
1Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, Taipei 10449, Taiwan.
Abstract:
BCR-ABL, a fusion protein kinase, is a druggable target exclusively expressed in patients with chronic myeloid leukemia (CML). Several anti-leukemia medicines targeting this protein have been developed in recent years. However, therapeutic options are limited for CML patients bearing multiple BCR-ABL1 mutations. Ponatinib (PON), a potent tyrosinase inhibitor, was one of the approved drugs for managing BCR-ABL1 T315I mutant disease. However, treatment of patients with PON reported severe side effects related to cardiovascular events. Asciminib (ASC) was the first allosteric inhibitor approved to target the myristoyl pocket of BCR-ABL protein to inhibit protein activity. The different mechanism of inhibition opens the possibility of co-exposure with both medicines. Reports on cardiovascular side effects due to the combination use of PON + ASC in pre-clinical and clinical studies are minimal. Thus, this study aimed to observe the potential cardiovascular-related side effect after co-exposure to ASC and PON using zebrafish as an animal model. In this study, zebrafish were acutely exposed to both compounds. The cardiovascular physiology parameters and gene expression related to cardiovascular development were evaluated. We demonstrate that combining ASC with PON at no observed effect concentration (NOEC) did not cause any significant change in the cardiac performance parameter in zebrafish. However, a significant increase in nkx2.5 expression level and a substantial decrease in blood flow velocity were recorded, suggesting that combining these compounds at NOEC can cause mild cardiovascular-related side effects.
Insights
Combining asciminib (ASC) and ponatinib (PON) for chronic myeloid leukemia (CML) showed no significant impact on cardiac performance in zebrafish. However, mild cardiovascular side effects were observed, including altered gene expression and reduced blood flow.
Area of Science:
- Biomedical Science
- Pharmacology
- Cardiovascular Research
Background:
- BCR-ABL fusion protein kinase is a key target in chronic myeloid leukemia (CML).
- Ponatinib (PON) and Asciminib (ASC) are approved drugs targeting BCR-ABL, but PON has cardiovascular risks.
- The combination of PON and ASC for BCR-ABL mutations requires investigation due to limited data on cardiovascular side effects.
Purpose of the Study:
- To evaluate potential cardiovascular side effects of combined Asciminib (ASC) and Ponatinib (PON) exposure.
- To utilize zebrafish as an animal model for assessing cardiovascular physiology and gene expression.
Main Methods:
- Zebrafish were acutely exposed to a combination of ASC and PON at their no observed effect concentration (NOEC).
- Cardiovascular physiology parameters, including cardiac performance and blood flow velocity, were measured.
- Gene expression analysis focused on markers related to cardiovascular development, specifically *nkx2.5*.
Main Results:
- Combined ASC and PON exposure at NOEC did not significantly alter cardiac performance parameters in zebrafish.
- A significant upregulation of *nkx2.5* gene expression was observed.
- A substantial decrease in blood flow velocity was recorded in the co-exposed zebrafish.
Conclusions:
- Co-exposure to ASC and PON at NOEC in zebrafish may induce mild cardiovascular-related side effects.
- The observed changes in *nkx2.5* expression and blood flow velocity warrant further investigation into the cardiovascular safety of this drug combination.
