| WP-1034, a novel JAK-STAT inhibitor, with proapoptotic and antileukemic activity in acute myeloid leukemia (AML). | |
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MedLine Citation:
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PMID: 16158916 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cytokine stimulation induces proliferation and growth of acute myeloid leukemia (AML) blasts and high levels of cytokines have been associated with poor prognosis in AML. The Jak-Stat pathway constitutes a major mediator of cytokine activity. We investigated whether WP-1034, a novel Jak-Stat inhibitor, is active against AML blasts. OCIM2 and fresh AML cells were incubated with 1 to 6 microM WP-1034 to determine its effect on proliferation. WP-1034 effectively inhibited proliferation of OCIM2 cells and fresh AML samples. We then analyzed the expressions of Stat 1, 3, and 5, as well as Phospho-Stat 1, 3, and 5 by Western immunoblotting after incubation of OCIM2 cells without and with 1 to 10 microM WP-1034 for 2 hours, and at 5 microM from 20 minutes up to 4 hours and found that WP-1034 blocked Stat 3 and 5 activation. Analysis of cell cycle status by PI staining and flow cytometry showed that WP-1034 caused cell cycle arrest of OCIM2 cells in sub-Go phase. We then evaluated the induction of apoptosis of OCIM2 cells following incubation with WP-1034 at 3 to 6 microM by annexin V-CY5 assay and analyzed caspase 3 and PARP cleavage using Western immunoblotting. We found that WP-1034 induced apoptosis of OCIM2 cells and that induction of apoptosis involved cleavage of caspase 3 and the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP). Taken together, our data suggest that WP-1034 is a potent inhibitor of AML cell proliferation by inhibition of Stat 3 and 5 and induction of caspase-dependent apoptosis. |
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Authors:
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Stefan Faderl; Alessandra Ferrajoli; David Harris; Quin Van; Waldemar Priebe; Zeev Estrov |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Anticancer research Volume: 25 ISSN: 0250-7005 ISO Abbreviation: Anticancer Res. Publication Date: 2005 May-Jun |
Date Detail:
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Created Date: 2005-09-14 Completed Date: 2005-11-02 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8102988 Medline TA: Anticancer Res Country: Greece |
Other Details:
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Languages: eng Pagination: 1841-50 Citation Subset: IM |
Affiliation:
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The Department of Leukemia of The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acrylamides
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pharmacology* Acute Disease Adult Aged Antineoplastic Agents / pharmacology Apoptosis / drug effects* Caspase 3 Caspases / metabolism Cell Cycle / drug effects Cell Growth Processes / drug effects Cell Line, Tumor DNA-Binding Proteins / antagonists & inhibitors* Enzyme Activation / drug effects Female Humans Janus Kinase 1 Leukemia, Erythroblastic, Acute / drug therapy, enzymology, pathology Leukemia, Myeloid / drug therapy*, enzymology, pathology Male Milk Proteins / antagonists & inhibitors* Nitriles / pharmacology* Protein Kinase Inhibitors / pharmacology Protein-Tyrosine Kinases / antagonists & inhibitors* STAT3 Transcription Factor STAT5 Transcription Factor Signal Transduction / drug effects Trans-Activators / antagonists & inhibitors* |
| Chemical | |
Reg. No./Substance:
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0/Acrylamides; 0/Antineoplastic Agents; 0/DNA-Binding Proteins; 0/Milk Proteins; 0/Nitriles; 0/Protein Kinase Inhibitors; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/STAT5 Transcription Factor; 0/Trans-Activators; 0/WP-1034; EC 2.7.1.112/JAK1 protein, human; EC 2.7.10.1/Janus Kinase 1; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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