Inhibition of phospholipase D by agents that inhibit cell growth.
The phospholipases are an important class of enzymes for growth factor and oncogene intracellular signalling. The anti-tumor drug suramin was found to inhibit phosphatidylcholine hydrolysis and trans-phosphatidylation by solubilized rat brain phospholipase D (PLD) with an IC50 of 15 microM. An azo analogue of suramin, which is a considerably more potent inhibitor of phosphatidylinositol phospholipase C (PIPLC) than suramin, inhibited PLD with and IC50 of 58 microM. D-609, a xanthogenate compound with in vitro antitumor activity, inhibited PLD with an IC50 of 820 microM. The cytotoxic aminosteroid compound U-73, 122 was a weaker inhibitor of PLD with an IC50 of 78 microM. However, U-73, 122 was a more potent inhibitor of PLD in fibroblast membranes with an IC50 of 25 microM, while suramin was less active with an IC50 of 4.2 mM. The antitumor ether lipid drug ET-18-OCH3 did not inhibit solubilized or membrane PLD although it is a potent inhibitor of PIPLC. The results of the study show that the compounds tested have different abilities to inhibit PIPLC and PLD. Access of hydrophilic drugs to membrane PLD may be a limiting factor to their inhibitory activity.
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Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson 85724.
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D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001391:Azo Compounds / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D004963:Estrenes / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D009636:Norbornanes; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D010742:Phospholipid Ethers / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D013498:Suramin / Q000494:pharmacology*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001391:Azo Compounds; D001952:Bridged-Ring Compounds; D004963:Estrenes; D009636:Norbornanes; D010742:Phospholipid Ethers; D011760:Pyrrolidinones; D013859:Thiocarbamates; D013871:Thiones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C026659:edelfosine; C046498:tricyclodecane-9-yl-xanthogenate; D013498:Suramin; D010739:Phospholipase D