| The selective protein kinase C beta inhibitor enzastaurin induces apoptosis in cutaneous T-cell lymphoma cell lines through the AKT pathway. | |
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MedLine Citation:
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PMID: 16645590 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Enzastaurin displays pro-apoptotic properties against a spectrum of malignancies and is currently being investigated in clinical trials. We have investigated the effects of enzastaurin on the viability of the cutaneous T-cell lymphoma cell lines HuT-78 and HH by using 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, cell cycle analysis, propidium iodide and annexin-V staining, and caspase-3-mediated proteolytic activation. Enzastaurin-treatment decreased cell viability, increased annexin V-FITC-positive cells, and increased the proportion of sub-G1 populations in both cell lines that was not reversed by the T-cell growth stimulating cytokines IL-2, IL-7, IL-15. Enzastaurin-induced cell death involved caspase-3-activated cleavage of poly(ADP-ribose) polymerase that was inhibited by the pan-caspase inhibitor ZVAD-fmk, whereas the increase in sub-G1 population was only partially inhibited by ZVAD-fmk. Furthermore, enzastaurin downregulated AKT activity and its downstream effectors GSK3beta and ribosomal protein S6. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the growth and survival of hematologic malignancies and inhibition of this pathway is considered as a therapeutic target. Protein kinase C activation contributes to PI3K/AKT activation, but it is unknown how enzastaurin may interfere with signaling through this pathway. These results demonstrate that enzastaurin, at clinically achievable concentrations, induces apoptosis and affects AKT signaling, and provide a rationale for further in vivo studies addressing the therapeutic efficacy in cutaneous T-cell lymphoma patients. |
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Authors:
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Christiane Querfeld; Mujahid A Rizvi; Timothy M Kuzel; Joan Guitart; Alfred Rademaker; Simran S Sabharwal; Nancy L Krett; Steven T Rosen |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-04-27 |
Journal Detail:
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Title: The Journal of investigative dermatology Volume: 126 ISSN: 0022-202X ISO Abbreviation: J. Invest. Dermatol. Publication Date: 2006 Jul |
Date Detail:
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Created Date: 2006-06-16 Completed Date: 2006-08-01 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0426720 Medline TA: J Invest Dermatol Country: United States |
Other Details:
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Languages: eng Pagination: 1641-7 Citation Subset: IM |
Affiliation:
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Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. c-querfeld@northwestern.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects*,
physiology Caspases / analysis, physiology Cell Cycle / drug effects, physiology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Enzyme Activation / drug effects, physiology Enzyme Inhibitors / pharmacology* Gene Expression Regulation, Neoplastic / drug effects Glycogen Synthase Kinase 3 / metabolism Humans Indoles / pharmacology* Lymphoma, T-Cell, Cutaneous / enzymology, pathology* Phosphorylation / drug effects Poly(ADP-ribose) Polymerases / analysis, physiology Protein Kinase C / antagonists & inhibitors* Proto-Oncogene Proteins c-akt / genetics, physiology* Ribosomal Protein S6 / analysis Signal Transduction / physiology* Skin Neoplasms / enzymology, pathology* |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Indoles; 0/Ribosomal Protein S6; 0/enzastaurin; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.1.-/protein kinase C beta; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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