| Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism. | |
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MedLine Citation:
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PMID: 12384435 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The effects of combined exposure to the checkpoint abrogator UCN-01 and pharmacologic MEK1/2 inhibitors were examined in human multiple myeloma (MM) cell lines. Treatment of RPMI8226, NCI-H929, and U266 MM cells with a minimally toxic concentration of UCN-01 (150 nM) for 24 hours resulted in mitogen-activated protein (MAP) kinase activation, an effect that was blocked by coadministration of the MEK1/2 inhibitor PD184352. These events were accompanied by enhanced activation of p34(cdc2) and a marked increase in mitochondrial damage (loss of DeltaPsim; cytochrome c and Smac/DIABLO (direct IAP binding protein with low pI) release), poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis. PD184352/UCN-01 also dramatically reduced clonogenic survival in each of the MM cell lines. In contrast to As(2)0(3), apoptosis induced by PD184352/UCN-01 was not blocked by the free-radical scavenger N-acetyl-L-cysteine. Whereas exogenous interleukin 6 substantially prevented dexamethasone-induced lethality in MM cells, it was unable to protect them from PD184352/UCN-01-induced apoptosis despite enhancing Akt activation. Insulinlike growth factor 1 (IGF-1) also failed to diminish apoptosis induced by this drug regimen. MM cell lines selected for a high degree of resistance to doxorubicin, melphalan, or dexamethasone, or displaying resistance secondary to fibronectin-mediated adherence, remained fully sensitive to PD184352/UCN-01-induced cell death. Finally, primary CD138(+) MM cells were also susceptible to UCN-01/MEK inhibitor-mediated apoptosis. Together, these findings suggest that simultaneous disruption of cell cycle and MEK/MAP kinase signaling pathways provides a potent stimulus for mitochondrial damage and apoptosis in MM cells, and also indicate that this strategy bypasses the block to cell death conferred by several other well-described resistance mechanisms. |
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Authors:
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Yun Dai; Terry H Landowski; Steven T Rosen; Paul Dent; Steven Grant |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Blood Volume: 100 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2002 Nov |
Date Detail:
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Created Date: 2002-10-17 Completed Date: 2002-12-10 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 3333-43 Citation Subset: AIM; IM |
Affiliation:
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Division of Hematology/Oncology, Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alkaloids
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pharmacology* Apoptosis / drug effects* Benzamides / pharmacology Bone Marrow Cells / drug effects, pathology CDC2 Protein Kinase / metabolism Cell Adhesion / drug effects Cell Cycle / drug effects* Dexamethasone / pharmacology Doxorubicin / pharmacology Drug Resistance, Multiple Drug Resistance, Neoplasm* Drug Synergism Enzyme Activation / drug effects Enzyme Inhibitors / pharmacology* Free Radical Scavengers / pharmacology Humans Insulin-Like Growth Factor I / pharmacology Interleukin-6 / pharmacology, physiology MAP Kinase Kinase 1 MAP Kinase Kinase 2 MAP Kinase Signaling System / drug effects* Melphalan / pharmacology Membrane Glycoproteins / analysis Mitochondria / drug effects, pathology Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*, physiology Multiple Myeloma / enzymology, pathology* Neoplasm Proteins / antagonists & inhibitors*, physiology Protein-Serine-Threonine Kinases / antagonists & inhibitors*, physiology Protein-Tyrosine Kinases / antagonists & inhibitors*, physiology Proteoglycans / analysis Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-akt Staurosporine / analogs & derivatives Syndecan-1 Syndecans Tumor Cells, Cultured / drug effects, pathology Tumor Stem Cell Assay |
| Grant Support | |
ID/Acronym/Agency:
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CA 63753/CA/NCI NIH HHS; CA 83705/CA/NCI NIH HHS; CA 88906/CA/NCI NIH HHS; DK 52855/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; 0/Alkaloids; 0/Benzamides; 0/Enzyme Inhibitors; 0/Free Radical Scavengers; 0/Interleukin-6; 0/Membrane Glycoproteins; 0/Neoplasm Proteins; 0/Proteoglycans; 0/Proto-Oncogene Proteins; 0/SDC1 protein, human; 0/Syndecan-1; 0/Syndecans; 112953-11-4/7-hydroxystaurosporine; 148-82-3/Melphalan; 23214-92-8/Doxorubicin; 50-02-2/Dexamethasone; 62996-74-1/Staurosporine; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.-/MAP2K1 protein, human; EC 2.7.1.-/MAP2K2 protein, human; EC 2.7.1.37/AKT1 protein, human; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.22/CDC2 Protein Kinase; EC 2.7.12.2/MAP Kinase Kinase 1; EC 2.7.12.2/MAP Kinase Kinase 2; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
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