A metabolite of an antineoplastic ether phospholipid may inhibit transmembrane signalling via protein kinase C.
In our search for the mechanisms by which the drug 1-O-alkyl-2-O-methylglycero-3-phosphocholine (AMG-PC) inhibits tumor growth and metastasis, we have detected a metabolite, 1-O-alkyl-2-O-methylglycerol (AMG), in membranes of MO4 mouse fibrosarcoma cells grown in the presence of the drug. Synthetic AMG inhibited the activation of highly purified human protein kinase C by diacylglycerol in the presence of phosphatidylserine. Furthermore, AMG also inhibited the receptor-specific binding of 3H-phorbol-12,13-dibutyrate to human HL-60 promyeloid leukemia cells in a dose-dependent fashion. AMG-PC was not effective or much less so in these assays. We suggest that interaction of the metabolite AMG with protein kinase C may inhibit stimulus-response coupling in tumor cells and may thus potentially contribute to the mechanism by which AMG-PC exerts its anticancer activities.
van Blitterswijk
W J
WJ
Division of Cell Biology, The Netherlands Cancer Institute (Antoni van Leeuwenhoek-Huis), Amsterdam.
van der Bend
R L
RL
Kramer
I M
IM
Verhoeven
A J
AJ
Hilkmann
H
H
de Widt
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D005354:Fibrosarcoma; D005995:Glyceryl Ethers / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009361:Neoplasm Invasiveness; D010703:Phorbol Esters / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
D000970:Antineoplastic Agents; D005995:Glyceryl Ethers; D010703:Phorbol Esters; D010742:Phospholipid Ethers; D011493:Protein Kinase C