title: A self-assembling protein kinase C inhibitor.
abstract: Previous studies have described a dicationic anticarcinoma agent that can chemically assemble in situ from monocationic phosphonium salts. The chemical combination of these monocationic precursors in the micromolar concentration range, occurring after their uptake by cells, was probably responsible for their synergistic inhibition of cell growth and for their selective cytotoxicity to Ehrlich ascites murine carcinoma cells relative to untransformed epithelial cells. Here, we report that the dicationic product that forms in this assembly reaction is an in vitro inhibitor of protein kinase C (PKC) alpha and beta 1 isoforms, exhibiting IC50 values of 20.4 microM and 35 microM, respectively. The monocationic precursors proved to be much weaker inhibitors of PKC (IC50 values greater than 200 microM). When PKC is exposed to combinations of the two precursors, the enzymatic activity decreases steadily as a function of time. Using dose-response data and HPLC kinetic studies, we show that when the two precursor compounds are added as a combination to PKC under these conditions, the rate of formation of the inhibitory product follows the observed time course of decline in PKC activity under identical conditions. We discuss the possibility that antiproliferative effects against carcinoma cells of the preformed dication and of the combined monocationic precursors involve inhibition of PKC.
authors.affiliation: Columbia University, Institute of Cancer Research, New York, NY 10032.
authors.forename: S A
authors.initials: SA
authors.lastname: Rotenberg
authors.forename: T
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: J S
authors.initials: JS
authors.lastname: Jaworski
authors.forename: I B
authors.initials: IB
authors.lastname: Weinstein
authors.forename: D
authors.initials: D
authors.lastname: Rideout
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007700:Kinetics; D051379:Mice; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000302:isolation & purification
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D009943:Organophosphorus Compounds; D011493:Protein Kinase C