Inhibition of phospholipid/Ca2+-dependent protein kinase and phosphorylation of leukemic cell proteins by CP-46,665-1, a novel antineoplastic lipoidal amine.
CP-46,665-1, an antineoplastic lipoidal amine, was found to inhibit phospholipid/Ca2+-dependent protein kinase (PL/Ca-PK, or protein kinase C), with an IC50 (concentration causing a 50% inhibition) of 10 microM. Its inhibition of the enzyme was reversed by phosphatidylserine, but not by Ca2+. The agent also inhibited the enzyme activity which was further augmented by 12-0-tetradecanoylphorbol-13-acetate (TPA), mezerein or diolein. Phosphorylation of endogenous proteins from HL-60 cells by the enzyme, with or without being further augmented by TPA, was inhibited by CP-46,665-1 as well as by alkyllysophospholipid (an antineoplastic agent). CP-46,665-1, while without effect on cyclic AMP-dependent protein kinase, also inhibited myosin light chain kinase (a calmodulin/Ca2+-dependent protein kinase). The present findings suggest that inhibition of the Ca2+-effector enzymes may be related in part to the antimetastatic activity of the lipoidal amine.
Shoji
M
M
Vogler
W R
WR
Kuo
J F
JF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011817:Rabbits; D013552:Swine
D000970:Antineoplastic Agents; D002273:Carcinogens; D009363:Neoplasm Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C038408:CP 46665; D011494:Protein Kinases; D011493:Protein Kinase C