MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine

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• 作者：Jeng-Wei Lu ; Yu-Min Lin ; Yen-Ling Lai ; Chien-Yuan Chen ; Chung-Yi Hu…
• 关键词：Acute myeloid leukemia ; MK ; 2206 ; Mcl ; 1 ; GSK3β ; AKT inhibitor
• 刊名：Medical Oncology
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：32
• 期：7
• 全文大小：1,425 KB
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• 作者单位：Jeng-Wei Lu (1)
  Yu-Min Lin (1)
  Yen-Ling Lai (1)
  Chien-Yuan Chen (4)
  Chung-Yi Hu (1) (3)
  Hwei-Fang Tien (4)
  Da-Liang Ou (2)
  Liang-In Lin (1) (3)
  
  1. Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
  4. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  3. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
  2. Department of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
  
• 刊物主题：Oncology; Hematology; Pathology; Internal Medicine;
• 出版者：Springer US
• ISSN：1559-131X

文摘

Genetic alterations in the PI3K/AKT cascade have been linked to various human cancers including acute myeloid leukemia (AML) and have emerged to be promising targets for treatment. In this study, we explored the molecular mechanism and clinical implication of a specific allosteric AKT inhibitor, MK-2206, in the treatment of AML. Four leukemia cell lines, MV-4-11, MOLM-13, OCI/AML3, and U937, were used. Apoptosis and cell cycle distribution were determined by flow cytometry analysis. Expression of anti-apoptotic protein family and glycogen synthase kinase 3β (GSK3β) signaling was determined by western blotting. Drug combination effects of MK-2206 with cytarabine were evaluated by cell proliferation assay, and the combination index values were calculated by CompuSyn software. MK-2206 had no effect on normal peripheral blood mononuclear cells, but induced G₁-phase arrest and apoptosis in leukemia cells. Among anti-apoptotic Bcl-2 family members, only myeloid cell leukemia-1 (Mcl-1) was significantly suppressed. Mcl-1 suppression by MK-2206 was closely associated with decreased GSK3β phosphorylation at Ser9, an event leads to GSK3β activation. Furthermore, the effect of MK-2206 on Mcl-1 downregulation was abolished by GSK3β inhibitor, lithium chloride and proteasome inhibitor, MG-132, suggesting that MK-2206 acted through a GSK3β-mediated, proteasome-dependent protein degradation. In addition, co-administration of MK-2206 with cytarabine could enhance the cytotoxic efficacy of cytarabine in leukemia cell lines. In conclusion, we have demonstrated that MK-2206 is an active agent in AML and its efficacy as in combination with cytarabine is implicated.