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Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death
Sook-Kyoung Heo1, Eui-Kyu Noh2, Jeong Yi Kim1
1Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 682-060, Republic of Korea.
Abstract:
Dasatinib and radotinib are oral BCR-ABL tyrosine kinase inhibitors that were developed as drugs for the treatment of chronic myeloid leukemia. We report here that the c-KIT (CD117) targeting with dasatinib and radotinib promotes acute myeloid leukemia (AML) cell death, and c-KIT endocytosis is essential for triggering c-KIT-positive AML cell death by dasatinib and radotinib during the early stages. In addition, dasatinib and radotinib reduce heat shock protein 90β (HSP90β) expression and release Apaf-1 in c-KIT-positive AML cells. Finally, this activates a caspase-dependent apoptotic pathway in c-KIT-positive AML cells. Moreover, the inhibition of c-KIT endocytosis by dynamin inhibitor (DY) reversed cell viability and c-KIT expression by dasatinib and radotinib. HSP90β expression was recovered by DY in c-KIT-positive AML cells as well. Furthermore, the effect of radotinib on c-KIT and HSP90β showed the same pattern in a xenograft animal model using HEL92.1.7 cells. Therefore, dasatinib and radotinib promote AML cell death by targeting c-KIT. Taken together, these results indicate that dasatinib and radotinib treatment have a potential role in anti-leukemic therapy on c-KIT-positive AML cells.
Insights
Dasatinib and radotinib target c-KIT, inducing cell death in acute myeloid leukemia (AML). This BCR-ABL inhibitor action is crucial for anti-leukemic therapy in c-KIT-positive AML.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Dasatinib and radotinib are BCR-ABL tyrosine kinase inhibitors used for chronic myeloid leukemia.
- Acute myeloid leukemia (AML) is a heterogeneous cancer with various therapeutic targets.
Purpose of the Study:
- To investigate the efficacy of dasatinib and radotinib in targeting c-KIT in AML.
- To elucidate the mechanism of action of these drugs in c-KIT-positive AML cells.
Main Methods:
- Cell viability assays and western blotting were used to assess drug effects.
- c-KIT endocytosis was inhibited using a dynamin inhibitor (DY).
- A xenograft animal model was employed to evaluate drug efficacy in vivo.
Main Results:
- Dasatinib and radotinib promote cell death in c-KIT-positive AML by targeting c-KIT.
- c-KIT endocytosis is essential for drug-induced AML cell death.
- These drugs reduce heat shock protein 90β (HSP90β) expression and activate caspase-dependent apoptosis.
- Inhibition of c-KIT endocytosis reversed drug effects on cell viability and HSP90β expression.
Conclusions:
- Dasatinib and radotinib demonstrate potential as anti-leukemic agents for c-KIT-positive AML.
- Targeting c-KIT and its associated pathways offers a promising therapeutic strategy for AML.
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