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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2003-6-6
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pubmed:abstractText |
The chimeric bcr-abl tyrosine kinase is of crucial pathogenic importance in chronic myeloid leukemia (CML). As shown, bcr-abl activates the ras pathway by phosphorylation of adapter proteins such as Grb-2 and Crkl. Functional inhibition of p21ras might partially inhibit the mitogenic signaling by bcr-abl. By depletion of cellular mevalonate pools, p21ras proteins can be rendered non-functional as a result of deficient post-translational protein farnesylation. We investigated the pharmacologic effect of mevalonate depletion by lovastatin in conjunction with interferon-alpha 2b (INF-alpha 2b) in bcr-abl positive K562 cells. At various concentrations, both drugs synergistically reduced cell proliferation of CML line K562 in a liquid culture system as well as clonal growth of colony forming units in a patient with newly diagnosed CML. Lovastatin and IFN-alpha 2b in combination led to cell cycle arrest and resulted in significant reduction of phosphorylation on tyrosine, serine, and threonine protein residues. IFN-alpha 2b alone showed little effect on protein phosphorylation but strongly enhanced lovastatin driven loss of phosphorylation. Subsequently, DNA fragmentation occurred in 50% of cells. In conclusion, exposure to IFN-alpha 2b and lovastatin synergistically inhibited proliferation of bcr-abl positive cells and resulted in loss of protein phosphorylation and subsequent apoptosis in K562 cells. Our in vitro model suggests further investigations are required of the potential value of HMG-CoA reductase inhibitors as adjunct to therapy of CML with interferon.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Fusion Proteins, bcr-abl,
http://linkedlifedata.com/resource/pubmed/chemical/HRAS protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxymethylglutaryl-CoA...,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Lovastatin,
http://linkedlifedata.com/resource/pubmed/chemical/Mevalonic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins p21(ras),
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Threonine,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/interferon alfa-2b
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1019-6439
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
23
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
151-8
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:12792788-Antineoplastic Agents,
pubmed-meshheading:12792788-Apoptosis,
pubmed-meshheading:12792788-Cell Cycle,
pubmed-meshheading:12792788-Cell Division,
pubmed-meshheading:12792788-Cell Line, Tumor,
pubmed-meshheading:12792788-DNA Fragmentation,
pubmed-meshheading:12792788-Dose-Response Relationship, Drug,
pubmed-meshheading:12792788-Flow Cytometry,
pubmed-meshheading:12792788-Fusion Proteins, bcr-abl,
pubmed-meshheading:12792788-Humans,
pubmed-meshheading:12792788-Hydroxymethylglutaryl-CoA Reductase Inhibitors,
pubmed-meshheading:12792788-Interferon-alpha,
pubmed-meshheading:12792788-K562 Cells,
pubmed-meshheading:12792788-Leukemia, Myelogenous, Chronic, BCR-ABL Positive,
pubmed-meshheading:12792788-Lovastatin,
pubmed-meshheading:12792788-Mevalonic Acid,
pubmed-meshheading:12792788-Phosphorylation,
pubmed-meshheading:12792788-Protein Prenylation,
pubmed-meshheading:12792788-Protein Processing, Post-Translational,
pubmed-meshheading:12792788-Proto-Oncogene Proteins p21(ras),
pubmed-meshheading:12792788-Recombinant Proteins,
pubmed-meshheading:12792788-Serine,
pubmed-meshheading:12792788-Threonine,
pubmed-meshheading:12792788-Time Factors,
pubmed-meshheading:12792788-Tyrosine
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pubmed:year |
2003
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pubmed:articleTitle |
Synergistic growth inhibitory effects of interferon-alpha and lovastatin on bcr-abl positive leukemic cells.
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pubmed:affiliation |
Department of Medicine, Hematology/Oncology, University of Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany. muellerc@uni-muenster.de
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pubmed:publicationType |
Journal Article
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