PUBLICATION
Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos
- Authors
- Lin, H.C., Saputra, F., Audira, G., Lai, Y.H., Roldan, M.J.M., Alos, H.C., Aventurado, C.A., Vasquez, R.D., Tsai, G.J., Lim, K.H., Hsiao, C.D.
- ID
- ZDB-PUB-221018-62
- Date
- 2022
- Source
- International Journal of Molecular Sciences 23(19): (Journal)
- Registered Authors
- Hsiao, Chung-Der
- Keywords
- anti-cancer drug, asciminib, cardiovascular toxicity, molecular docking, ponatinib, zebrafish
- MeSH Terms
-
- Animals
- Antineoplastic Agents*/toxicity
- Drug Resistance, Neoplasm/genetics
- Fusion Proteins, bcr-abl/genetics
- Imidazoles
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive*/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive*/genetics
- Monophenol Monooxygenase
- Niacinamide/analogs & derivatives
- Protein Kinase Inhibitors/pharmacology
- Pyrazoles
- Pyridazines*/toxicity
- Zebrafish
- PubMed
- 36233014 Full text @ Int. J. Mol. Sci.
Citation
Lin, H.C., Saputra, F., Audira, G., Lai, Y.H., Roldan, M.J.M., Alos, H.C., Aventurado, C.A., Vasquez, R.D., Tsai, G.J., Lim, K.H., Hsiao, C.D. (2022) Investigating Potential Cardiovascular Toxicity of Two Anti-Leukemia Drugs of Asciminib and Ponatinib in Zebrafish Embryos. International Journal of Molecular Sciences. 23(19):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping