PMID- 27477352
OWN - NLM
STAT- MEDLINE
DCOM- 20170321
LR  - 20170806
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 789
DP  - 2016 Oct 15
TI  - Radotinib inhibits acute myeloid leukemia cell proliferation via induction of 
      mitochondrial-dependent apoptosis and CDK inhibitors.
PG  - 280-290
LID - S0014-2999(16)30489-7 [pii]
LID - 10.1016/j.ejphar.2016.07.049 [doi]
AB  - 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.
CI  - Copyright (c) 2016 Elsevier B.V. All rights reserved.
FAU - Heo, Sook-Kyoung
AU  - Heo SK
AD  - Biomedical Research Center, Ulsan University Hospital, University of Ulsan 
      College of Medicine, Ulsan 682-060, Republic of Korea.
FAU - Noh, Eui-Kyu
AU  - Noh EK
AD  - Department of Hematology and Oncology, Ulsan University Hospital, University of 
      Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
FAU - Gwon, Gi-Dong
AU  - Gwon GD
AD  - Biomedical Research Center, Ulsan University Hospital, University of Ulsan 
      College of Medicine, Ulsan 682-060, Republic of Korea.
FAU - Kim, Jeong Yi
AU  - Kim JY
AD  - Biomedical Research Center, Ulsan University Hospital, University of Ulsan 
      College of Medicine, Ulsan 682-060, Republic of Korea.
FAU - Jo, Jae-Cheol
AU  - Jo JC
AD  - Department of Hematology and Oncology, Ulsan University Hospital, University of 
      Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
FAU - Choi, Yunsuk
AU  - Choi Y
AD  - Department of Hematology and Oncology, Ulsan University Hospital, University of 
      Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
FAU - Koh, SuJin
AU  - Koh S
AD  - Department of Hematology and Oncology, Ulsan University Hospital, University of 
      Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
FAU - Baek, Jin Ho
AU  - Baek JH
AD  - Department of Hematology and Oncology, Ulsan University Hospital, University of 
      Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
FAU - Min, Young Joo
AU  - Min YJ
AD  - Department of Hematology and Oncology, Ulsan University Hospital, University of 
      Ulsan College of Medicine, Ulsan 682-714, Republic of Korea.
FAU - Kim, Hawk
AU  - Kim H
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20160728
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cyclins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/*drug effects
MH  - Caspase 3/metabolism
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cyclin-Dependent Kinases/*antagonists & inhibitors
MH  - Cyclins/metabolism
MH  - Enzyme Activation/drug effects
MH  - Female
MH  - G1 Phase Cell Cycle Checkpoints/drug effects
MH  - Humans
MH  - Leukemia, Myeloid, Acute/drug therapy/metabolism/*pathology
MH  - Male
MH  - Middle Aged
MH  - Mitochondria/*drug effects
MH  - Protein Kinase Inhibitors/*pharmacology/therapeutic use
MH  - Resting Phase, Cell Cycle/drug effects
OTO - NOTNLM
OT  - AML cell death
OT  - Acute myeloid leukemia
OT  - Anti-leukemic activity
OT  - G(0)/G(1) phase cell cycle arrest
OT  - Mitochondrial-dependent apoptotic pathway
OT  - Radotinib
OT  - Radotinib (PubChem CID: 16063245)
EDAT- 2016/08/02 06:00
MHDA- 2017/03/23 06:00
CRDT- 2016/08/02 06:00
PHST- 2016/04/11 00:00 [received]
PHST- 2016/07/22 00:00 [revised]
PHST- 2016/07/27 00:00 [accepted]
PHST- 2016/08/02 06:00 [entrez]
PHST- 2016/08/02 06:00 [pubmed]
PHST- 2017/03/23 06:00 [medline]
AID - S0014-2999(16)30489-7 [pii]
AID - 10.1016/j.ejphar.2016.07.049 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2016 Oct 15;789:280-290. doi: 10.1016/j.ejphar.2016.07.049. Epub 
      2016 Jul 28.