Radotinib induces high cytotoxicity in c-KIT positive acute myeloid leukemia cells

Previously, we reported that radotinib, a BCR-ABL1 tyrosine kinase inhibitor, induced cytotoxicity in acute myeloid leukemia (AML) cells. However, the effects of radotinib in the subpopulation of c-KIT-positive AML cells were unclear. We observed that low-concentration radotinib had more potent cyto...

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Bibliographic Details
Published in:European journal of pharmacology 2017-06, Vol.804, p.52-56
Main Authors: Heo, Sook-Kyoung, Noh, Eui-Kyu, Kim, Jeong Yi, Jo, Jae-Cheol, Choi, Yunsuk, Koh, SuJin, Baek, Jin Ho, Min, Young Joo, Kim, Hawk
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Adolescent
Adult
Aged
Aged, 80 and over
Anti-leukemic activity
Benzamides - pharmacology
Benzamides - therapeutic use
c-KIT
CD117
Cell Line, Tumor
Cytotoxicity
Female
Gene Expression Regulation, Leukemic - drug effects
Gene Expression Regulation, Neoplastic - drug effects
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - pathology
Male
Middle Aged
Proto-Oncogene Proteins c-kit - metabolism
Pyrazines - pharmacology
Pyrazines - therapeutic use
Radotinib
Radotinib (PubChem CID: 16063245)
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Summary:Previously, we reported that radotinib, a BCR-ABL1 tyrosine kinase inhibitor, induced cytotoxicity in acute myeloid leukemia (AML) cells. However, the effects of radotinib in the subpopulation of c-KIT-positive AML cells were unclear. We observed that low-concentration radotinib had more potent cytotoxicity in c-KIT-positive cells than c-KIT-negative cells from AML patients. To address this issue, cell lines with high c-KIT expression, HEL92.1.7, and moderate c-KIT expression, H209, were selected. HEL92.1.7 cells were grouped into intermediate and high c-KIT expression populations. The cytotoxicity of radotinib against the HEL92.1.7 cell population with intermediate c-KIT expression was not different from that of the population with high c-KIT expression. When H209 cells were grouped into c-KIT expression-negative and c-KIT expression-positive populations, radotinib induced cytotoxicity in the c-KIT-positive population, but not the c-KIT-negative population. Thus, radotinib induces cytotoxicity in c-KIT-positive cells, regardless of the c-KIT expression intensity. Therefore, radotinib induces significant cytotoxicity in c-KIT-positive AML cells, suggesting that radotinib is a potential target agent for the treatment of c-KIT-positive malignancies including AML.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2017.03.040