title: Radotinib inhibits acute myeloid leukemia cell proliferation via induction of mitochondrial-dependent apoptosis and CDK inhibitors.
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.
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea.
authors.forename: Sook-Kyoung
authors.initials: SK
authors.lastname: Heo
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Eui-Kyu
authors.initials: EK
authors.lastname: Noh
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea.
authors.forename: Gi-Dong
authors.initials: GD
authors.lastname: Gwon
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea.
authors.forename: Jeong Yi
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Jae-Cheol
authors.initials: JC
authors.lastname: Jo
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Yunsuk
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: SuJin
authors.initials: S
authors.lastname: Koh
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Min
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-060, Republic of Korea; Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 682-714, Republic of Korea. Electronic address: kimhawkmd@gmail.com.
authors.forename: Hawk
authors.initials: H
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016192:Resting Phase, Cell Cycle / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases; D053148:Caspase 3
keywords: AML cell death; Acute myeloid leukemia; Anti-leukemic activity; G(0)/G(1) phase cell cycle arrest; Mitochondrial-dependent apoptotic pathway; Radotinib; Radotinib (PubChem CID: 16063245)