title: PX-52, A novel inhibitor of 14 kDa secretory and 85 kDa cytosolic phospholipases A2.
abstract: Previously we reported that PGBx, a prostaglandin oligomer with anti-inflammatory activity, inhibited 14 kDa phospholipase A2 (PLA2) activity and blocked arachidonic acid mobilization in prelabeled human neutrophils (Biochim. Biophys. Acta 1006:272-277, 278-286, 1989) This study describes a new inhibitor of phospholipase A2, PX-52, that also blocks agonist induced arachidonic acid mobilization in prelabeled cells. PX-52, a fatty acid polymer, inhibited hydrolysis of 14C-oleate labeled E.coli by a variety of 14 kDa PLA2s including human PMN, sperm, synovial fluid and disc, as well as porcine pancreas, N. naja, and bee venom in a dose-dependent manner with IC50s ranging from 1.0-3.7 uM. Inhibition of activity was comparable at different Ca2+ concentrations, but was relieved by increasing substrate concentration or by methylation of PX-52. Hydrolysis of [14C]-arachidonyl phosphatidylcholine by 85 kDa, cytosolic PLA2 from U937 cells was similarly inhibited by PX-52, the IC50 = 5 uM. Arachidonic acid mobilization induced by A23187 in prelabeled human PMNs was blocked by PX-52; IC50 = 10-15 uM while concentrations of up to 80 uM oleate had no effect. These results demonstrate that PX-52 inhibits the in vitro activity of secretory and cytosolic PLA2s and agonist-induced arachidonic acid release from human cells. Given its ability to block the arachidonic acid cascade, PX-52 may be useful in the control of inflammation.
authors.affiliation: Department of Biochemistry & Molecular Biophysics, Virginia Commonwealth University, Richmond, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Franson
authors.forename: M D
authors.initials: MD
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D007405:Intervertebral Disc Displacement / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D019301:Oleic Acid / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011108:Polymers / Q000494:pharmacology*; D013094:Spermatozoa / Q000201:enzymology; D013552:Swine; D013582:Synovial Fluid / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011108:Polymers; D016718:Arachidonic Acid; D019301:Oleic Acid; D010741:Phospholipases A; D054467:Phospholipases A2