| The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations. | |
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MedLine Citation:
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PMID: 18071308 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PKC412 is a staurosporine derivative that inhibits several protein kinases including FLT3, and is highly anticipated as a novel therapeutic agent for acute myeloblastic leukemia (AML) carrying FLT3 mutations. In this study, we show that PKC412 exerts differential cell cycle effects on AML cells depending on the presence of FLT3 mutations. PKC412 elicits massive apoptosis without markedly affecting cell cycle patterns in AML cell lines with FLT3 mutations (MV4-11 and MOLM13), whereas it induces G2 arrest but not apoptosis in AML cell lines without FLT3 mutations (THP-1 and U937). In MV4-11 and MOLM13 cells, PKC412 inactivates Myt-1 and activates CDC25c, leading to the activation of CDC2. Activated CDC2 phosphorylates Bad at serine-128 and facilitates its translocation to the mitochondria, where Bad triggers apoptosis. In contrast, PKC412 inactivates CDC2 by inducing serine-216 phosphorylation and subsequent cytoplasmic sequestration of CDC25c in THP-1 and U937 cells. As a result, cells are arrested in the G2 phase of the cell cycle, but do not undergo apoptosis because Bad is not activated. The FLT3 mutation-dependent differential cell cycle effect of PKC412 is considered an important factor when PKC412 is combined with cell cycle-specific anticancer drugs in the treatment of cancer and leukemia. |
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Authors:
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T Odgerel; J Kikuchi; T Wada; R Shimizu; K Futaki; Y Kano; Y Furukawa |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-12-10 |
Journal Detail:
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Title: Oncogene Volume: 27 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-05-15 Completed Date: 2008-06-03 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 3102-10 Citation Subset: IM |
Affiliation:
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Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects,
genetics Cell Cycle / drug effects*, genetics Cell Line, Tumor Cell Proliferation / drug effects Cyclin B / metabolism Humans Leukemia, Myeloid, Acute / genetics*, pathology Mutation* Phosphorylation Serine / metabolism Signal Transduction / drug effects, genetics Staurosporine / analogs & derivatives*, pharmacology U937 Cells bcl-Associated Death Protein / metabolism fms-Like Tyrosine Kinase 3 / antagonists & inhibitors, genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/BAD protein, human; 0/CDC2 protein, human; 0/Cyclin B; 0/PKC412; 0/bcl-Associated Death Protein; 56-45-1/Serine; 62996-74-1/Staurosporine; EC 2.7.10.1/FLT3 protein, human; EC 2.7.10.1/fms-Like Tyrosine Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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