Radotinib inhibits acute myeloid leukemia cell proliferation via induction of mitochondrial-dependent apoptosis and CDK inhibitors

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Abstract

Radotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the second-line treatment of chronic myeloid leukemia. However, effects of radotinib on acute myeloid leukemia (AML) are unclear. In the present study, we observed that radotinib exerted cytotoxic effects on AML cells. Of the various AML cell lines examined (NB4, HL60, HEL 92.1.7, and THP-1), Kasumi-1 was the most sensitive to radotinib. Results of microarray analysis showed that 417 and 595 genes associated with apoptosis and cell cycle regulation, respectively, were differently expressed (i.e., showed >2-fold difference in expression). Radotinib-induced apoptosis involved the mitochondrial pathway. Moreover, radotinib increased the apoptosis of and induced caspase-3 activity in both Kasumi-1 cells and bone marrow cells (BMCs) obtained from patients with AML. Radotinib also increased cleaved caspase-3, caspase-7, and caspase-9 levels and decreased the number of proliferating Kasumi-1 cells and BMCs from patients with AML. In addition, radotinib induced G0/G1 phase arrest by inducing CDKIs p21 and p27 and by inhibiting CDK2, CDK4, and CDK6. These results indicate that radotinib induces caspase-dependent apoptosis and G0/G1 phase arrest in AML cells by regulating CDKI–CDK–cyclin cascade. Moreover, these results indicate that radotinib inhibits AML cell proliferation by inducing mitochondria-dependent apoptosis and CDKIs p21 and p27. To our knowledge, this is the first study to show that radotinib can be potentially used for the anti-leukemic therapy of patients with AML.

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