Synergistic antiproliferative effect of cis-diammine-dichloroplatinum (II) and a new anticancer agent, plasmanyl-(N-acyl)-ethanolamine, an inhibitor of protein kinase C.
The action of a new anticancer agent, the semisynthetic alkyl-phospholipid plasmanyl-(N-acyl)-ethanolamine (sPNAE), namely 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)-ethanolamine, on protein kinase C (PKC) was investigated, and it was found to inhibit in a dose-dependent manner PKC isolated from mouse brain. The inhibition was competitive with respect to phosphatidylserine (K(i) = 20 microM). Lyso-PNAE, a possible cell metabolite of sPNAE, also inhibited PKC. A two-site model was used to calculate the binding affinity and the number of binding sites for phorbol ester in a culture of human melanoma BRO cells. The values of Kd, the dissociation constant, were K'd = 0.5 nM and K"d = 72 nM, whereas the values of Bmax, the number of binding sites, were B'max = 4.6 x 10(4) sites cell-1, and B"max = 2.9 x 10(5) sites cell-1. sPNAE was able to reduce the affinity of BRO cells for phorbol ester with almost no changes in the number of binding sites: K'd = 1.6 nM, K"d = 557 nM, and B'max = 4 x 10(4), B"max = 1.9 x 10(5). These data suggest that sPNAE may inhibit PKC in intact cells. Since various inhibitors of PKC may enhance the antiproliferative activity of cis-diamminedichloroplatinum(II) (cis-DDP), we investigated the effect of the combination of sPNAE and cis-DDP on the proliferation of BRO cells. sPNAE synergistically enhanced the antiproliferative activity of cis-DDP.
Mikhaevich
I S
IS
Institute of Experimental Diagnosis and Therapy of Tumours, All-Union Cancer Research Centre, Russian Academy of Medical Sciences, Moscow.
Vlasenkova
N K
NK
Gerasimova
G K
GK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008545:Melanoma; D051379:Mice; D010713:Phosphatidylcholines / Q000494:pharmacology*; D010714:Phosphatidylethanolamines; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C078193:1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolamine; D011493:Protein Kinase C; D002945:Cisplatin