Inhibitors of coenzyme A-independent transacylase induce apoptosis in human HL-60 cells. 1996

J D Winkler, and T Eris, and C M Sung, and M Chabot-Fletcher, and R J Mayer, and M E Surette, and F H Chilton
Department of Immunopharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.

ET-18-O-CH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine) is an antiproliferative agent, blocking the growth of cancer cells both in vitro and in vivo. However, there is controversy regarding the mechanism leading to its antiproliferative effects. CoA-independent transacylase (CoA-IT) is an enzyme that remodels arachidonate between specific phospholipid donor and acceptor molecules in a variety of mammalian cells. ET-18-O-CH3 was found to be a potent inhibitor of CoA-IT (IC50, 0.5 microM), and kinetic analysis revealed that its inhibition was competitive with the lyso-phospholipid substrate. The goal of the current study was to explore the connection between inhibition of CoA-IT and antiproliferative effects using several structurally distinct inhibitors of CoA-IT. ET-18-O-CH3 and other inhibitors of CoA-IT were found to inhibit cell proliferation and thymidine incorporation into the DNA, as well as to induce apoptosis in human HL-60 monocytic leukemia cells. The mechanism of apoptosis induced by ET-18-O-CH3 appeared to be different from that induced by tumor necrosis factor; the former failed to activate NF-kappa B, whereas tumor necrosis factor did. Closer examination of the pharmacology of apoptosis in this model revealed that compounds that were structurally related to CoA-IT inhibitors, but lacked CoA-IT inhibitory activity, also failed to induce apoptosis. In addition, compounds that inhibited other enzymes that participate in arachidonic acid metabolism, cyclooxygenase, 5-lipoxygenase and phospholipase A2, did not induce apoptosis. Taken together, these results demonstrate that inhibition of CoA-IT can be linked to blockade of proliferation and the induction of apoptosis in HL-60 cells.

UI MeSH Term Description Entries
D010742 Phospholipid Ethers Phospholipids which have an alcohol moiety in ethereal linkage with a saturated or unsaturated aliphatic alcohol. They are usually derivatives of phosphoglycerols or phosphatidates. The other two alcohol groups of the glycerol backbone are usually in ester linkage. These compounds are widely distributed in animal tissues. Ether Phosphatidates,Ether Phospholipids,Glycerol Phosphate Ethers,Glycerophosphate Ethers,1-Alkyl-2-Acylphosphatidates,1 Alkyl 2 Acylphosphatidates,Ethers, Glycerol Phosphate,Ethers, Glycerophosphate,Ethers, Phospholipid,Phosphate Ethers, Glycerol,Phosphatidates, Ether,Phospholipids, Ether
D010743 Phospholipids Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides see GLYCEROPHOSPHOLIPIDS) or sphingosine (SPHINGOLIPIDS). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. Phosphatides,Phospholipid
D002455 Cell Division The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION. M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D003065 Coenzyme A CoA,CoASH
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000217 Acyltransferases Enzymes from the transferase class that catalyze the transfer of acyl groups from donor to acceptor, forming either esters or amides. (From Enzyme Nomenclature 1992) EC 2.3. Acyltransferase
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D016328 NF-kappa B Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA. Immunoglobulin Enhancer-Binding Protein,NF-kappa B Complex,Nuclear Factor kappa B,Transcription Factor NF-kB,kappa B Enhancer Binding Protein,Ig-EBP-1,NF-kB,NF-kappaB,Nuclear Factor-Kappab,Complex, NF-kappa B,Enhancer-Binding Protein, Immunoglobulin,Factor NF-kB, Transcription,Factor-Kappab, Nuclear,Ig EBP 1,Immunoglobulin Enhancer Binding Protein,NF kB,NF kappa B Complex,NF kappaB,NF-kB, Transcription Factor,Nuclear Factor Kappab,Transcription Factor NF kB
D016718 Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. (all-Z)-5,8,11,14-Eicosatetraenoic acid,Arachidonic Acid, (all-Z)-Isomer, 1-(14)C-Labeled,Arachidonic Acid, (all-Z)-isomer, 3H-Labeled,Arachidonic Acid, Ammonium Salt, (all-Z)-Isomer,Arachidonic Acid, Cerium Salt, (all-Z)-Isomer,Arachidonic Acid, Cesium Salt, (all-Z)-Isomer,Arachidonic Acid, Lithium Salt, (all-Z)-Isomer,Arachidonic Acid, Potassium Salt, (all-Z)-Isomer,Arachidonic Acid, Sodium Salt,Arachidonic Acid, Sodium Salt, (all-Z)-Isomer,Arachidonic Acid, Zinc Salt, (all-Z)-Isomer,Sodium Arachidonate,Vitamin F,Arachidonate, Sodium

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