title: Activation of protein kinase C by 1-beta-D-arabinofuranosylcytosine conjugates of phospholipid.
abstract: 1-beta-D-arabinofuranosylcytosine (ara-C) conjugates of phospholipid were shown to be highly antineoplastic against various tumor cells. In this study, we report that these conjugates are potent activators of protein kinase C (PKC, EC) in vitro. Although required Ca2+, PKC activation by the conjugates occurred even in the absence of phospholipid and diacylglycerol. Among the conjugates, 1-beta-D-arabino-furanosylcytosine 5'-diphosphate-rac-1-O-octadecyl-2-O-palmitoylglycerol [(ara-CDP-DL-PBA); ara-C conjugate of ether phospholipid], was employed to investigate its mode of activation, since ether phospholipid has been reported to be a regulator of the PKC. When PKC was activated by ara-CDP-DL-PBA, diacylglycerol enhanced its activity with 3-fold reduction of an apparent Ka value for ara-CDP-DL-PBA and no change in the Vmax. During the PKC activation by phosphatidylserine, ara-CDP-DL-PBA exhibited a synergistic effect on the activation. Studies on the relationship between the structures of ara-CDP-DL-PBA and their effects on PKC activity showed that phosphate group of ether lipid was important for its activation of PKC, and that conjugation of ara-C and ether lipid further enhanced the enzyme activity. These results suggest that the ara-C conjugate of phospholipid activates PKC in a co-operative manner with diacylglycerol and/or phosphatidylserine, however, the exact mechanism of the antineoplastic effect of ara-CDP-DL-PBA through PKC activation still remains speculative.
authors.affiliation: Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Nowon-Ku, Seoul 139-240, Korea.
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Jung
authors.forename: Chung-Il
authors.initials: CI
authors.lastname: Hong
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Bai
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Yu
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Kim
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003561:Cytarabine / Q000737:chemistry* / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004075:Diglycerides / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D010718:Phosphatidylserines / Q000737:chemistry / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011479:Protamines / Q000378:metabolism; D011493:Protein Kinase C / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004075:Diglycerides; D008565:Membrane Proteins; D010718:Phosphatidylserines; D010743:Phospholipids; D011479:Protamines; D003561:Cytarabine; D011493:Protein Kinase C