title: Compounds stimulating cytosolic phospholipase A2 activity with a combinational action mode.
abstract: The screening of small synthetic compound libraries is a useful means of identifying molecules that modulate various cellular responses. We screened more than 10,000 different small compounds and identified three synthetic compounds that stimulate arachidonic acid (AA) release in a combinational manner in neutrophil-like differentiated HL60 cells. These three compounds were designated as AARIC-1, -2, and -3, representing AA release inducing compounds-1, -2, and -3. Although AA release was not induced by any single one of these compounds, it was dramatically stimulated by the three compounds in combination. Moreover, the effect of combined treatment by these compounds on AA release was completely abolished by MAFP and AACOCF(3), specific cytosolic phospholipase A(2) inhibitors. Furthermore, we found that AARIC-3 stimulates cytosolic calcium influx, while AARIC-1 induces ERK activation. Taken together, we demonstrate a useful approach to the study of complicated and nonlinear intracellular signaling networks using small synthetic compounds in combination.
authors.affiliation: Medical Research Center for Cancer Molecular Therapy, College of Medicine, Dong-A University, Busan 602-714, Republic of Korea. yoesik@donga.ac.kr
authors.forename: Yoe-Sik
authors.initials: YS
authors.lastname: Bae
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Park
authors.forename: Ha-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyun Kyu
authors.initials: HK
authors.lastname: Kang
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Kwak
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.forename: Taehoon
authors.initials: T
authors.lastname: Lee
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism*; D001095:Arachidonic Acids / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D003600:Cytosol / Q000201:enzymology*; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D011688:Purinones / Q000737:chemistry / Q000494:pharmacology; D014316:Tritium
chemical_list: D000081:Acetamides; D001095:Arachidonic Acids; D001572:Benzofurans; D004791:Enzyme Inhibitors; D011688:Purinones; D014316:Tritium; D016718:Arachidonic Acid; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium