title: Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells.
abstract: Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI), is approved for the second-line treatment of chronic myeloid leukemia (CML) in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML) are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA). We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (ΔΨm) in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics.
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: Dong-Joon
authors.initials: DJ
authors.lastname: Yoon
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, Myongji Hospital, Gyeonggi-do, 412-270, Republic of Korea.
authors.forename: Jae-Hoo
authors.initials: JH
authors.lastname: Park
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.
authors.forename: Hawk
authors.initials: H
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D014212:Tretinoin / Q000494:pharmacology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C000606751:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl)-3-(4-pyrazin-2-ylpyrimidin-2-ylamino)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D039481:CD11b Antigen; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D014212:Tretinoin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases