title: Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity.
abstract: Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Sook-Kyoung
authors.initials: SK
authors.lastname: Heo
authors.affiliation: Division of Hematology and Hematological Malignancies, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 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, Republic of Korea.
authors.forename: Dong-Joon
authors.initials: DJ
authors.lastname: Yoon
authors.affiliation: Division of Hematology and Hematological Malignancies, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Jae-Cheol
authors.initials: JC
authors.lastname: Jo
authors.affiliation: Division of Hematology and Hematological Malignancies, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Jae-Hoo
authors.initials: JH
authors.lastname: Park
authors.affiliation: Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; Division of Hematology and Hematological Malignancies, Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Hawk
authors.initials: H
authors.lastname: Kim
mesh_terms: D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004357:Drug Synergism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D011743:Pyrimidines; D013844:Thiazoles; D014635:Valproic Acid; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib