| Effect of novel modulators of protein kinase C activity upon chemotherapy-induced differentiation and apoptosis in myeloid leukemic cells. | |
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MedLine Citation:
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PMID: 12187329 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Modulation of protein kinase C (PKC) activity has been demonstrated to either prevent or enhance drug-induced apoptosis in various tissue types. We tested four novel modulators of PKC activity in comparison to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) for the capability to affect differentiation, cell cycle progression and apoptosis in the human myeloid leukemia cell lines U937 and HL-60. Farnesyl thiotriazole (FTT) and N-(n-heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) are both direct activators of PKC, whereas 6-(2-(4-[(4-fluorophe-nyl)phenylmethylene]-1-piperidinyl)ethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (R59022) and [3-[2-[4-(bis-(4-fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quin-azolinone (R59949) are diacyl glycerol kinase inhibitors that activate PKC by enhancing the levels of the endogenous ligand diacyl glycerol. U937 cells displayed a slight reduction in the number of cells in G(2)/M cell cycle phase after exposure to FTT, SC-10, R59022 and R59949, respectively. In contrast, HL-60 cells demonstrated a largely unaltered cell cycle distribution. Whereas TPA treatment resulted in a strong induction of p21(WAF/CIP1), c-Fos and c-Jun levels, neither one of the novel PKC activators altered expression of these proteins. Consequently, we tested the ability of the activators to cause membrane translocation of PKC. While TPA treatment resulted in translocation of the PKC isoforms alpha, delta and epsilon, SC-10 and FTT failed to induce alterations in the PKC content of the membrane and cytosolic fractions, respectively. Expression of the beta(2)-integrin CD11c that is induced during TPA-mediated differentiation remained unaltered after exposure to SC-10 and was partly reduced after treatment with FTT. To further investigate the effect of these activators upon apoptosis in leukemic cells, HL-60 and U937 cells were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C) or etoposide (VP-16). Whereas TPA strongly reduced apoptosis in Ara-C- or VP-16-treated U937 cells, little if any reduction was observed after pretreatment with either FTT, SC-10, R59022 or R59949, respectively, in these cells. In contrast, TPA enhanced apoptosis in Ara-C- or VP-16-treated HL-60 cells. Interestingly, FTT and SC-10 demonstrated a protective effect in Ara-C-treated HL-60 cells. Taken together, these data suggest that the novel PKC activators FTT, SC-10, R59022 and R59949 exhibit modest biological effects upon leukemic blast cells, and are not capable of enhancing the apoptotic response of these cells to cytotoxic drugs. |
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Authors:
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Gerold Meinhardt; Elfriede Eppinger; Ralf Schmidmaier |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Anti-cancer drugs Volume: 13 ISSN: 0959-4973 ISO Abbreviation: Anticancer Drugs Publication Date: 2002 Aug |
Date Detail:
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Created Date: 2002-08-20 Completed Date: 2003-02-05 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9100823 Medline TA: Anticancer Drugs Country: England |
Other Details:
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Languages: eng Pagination: 725-33 Citation Subset: IM |
Copyright Information:
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Copyright 2002 Lippincott Williams & Wilkins. |
Affiliation:
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Medizinische Klinik Innenstadt, Department of Hematology/Oncology, Ludwig-Maximilians-University, 80336 Munich, Germany. geroldmeinhardt@yahoo.com.de |
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD11c
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biosynthesis Antigens, CD4 / biosynthesis Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Cell Cycle / drug effects Cell Differentiation / drug effects Diacylglycerol Kinase / antagonists & inhibitors Enzyme Activators / pharmacology* Enzyme Inhibitors / pharmacology Farnesol / analogs & derivatives*, pharmacology Flow Cytometry Genes, fos / drug effects Genes, jun / drug effects Humans Immunoblotting Isoenzymes / antagonists & inhibitors Leukemia, Myeloid / drug therapy, pathology* Naphthalenes / pharmacology Oncogene Protein p21(ras) / biosynthesis Piperidines / pharmacology Protein Kinase C / metabolism* Pyrimidinones / pharmacology Quinazolines / pharmacology Quinazolinones Sulfonamides / pharmacology Thiazoles / pharmacology Triazoles / pharmacology Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD11c; 0/Antigens, CD4; 0/Antineoplastic Agents; 0/Enzyme Activators; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/Naphthalenes; 0/Piperidines; 0/Pyrimidinones; 0/Quinazolines; 0/Quinazolinones; 0/Sulfonamides; 0/Thiazoles; 0/Triazoles; 102649-79-6/N-(m-heptyl)-5-chloro-1-naphthalenesulfonamide; 120166-69-0/R 59949; 156604-45-4/farnesylthiotriazole; 4602-84-0/Farnesol; 93076-89-2/R 59022; EC 2.7.1.107/Diacylglycerol Kinase; EC 2.7.11.13/Protein Kinase C; EC 3.6.5.2/Oncogene Protein p21(ras) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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