Inhibition of phospholipase C delta by hexadecylphosphorylcholine and lysophospholipids with antitumor activity.
The antineoplastic compound hexadecylphosphorylcholine (HPC) was shown to be a highly effective inhibitor of phospholipase C delta (PLC delta 1), with an I50 of about 30 nmol/mL (30 microM) in the presence and absence of 200 microM spermine. A number of lysophospholipids, of which HPC can be considered to be a structural analog, also inhibited PLC. Lysosphingomyelin, lysophosphatidylserine, and lysophosphatidylcholine exhibited I50 values of 15, 10, and 7 nmol/mL, respectively, in the presence of 200 microM spermine. The I50 values were increased to 21-53 nmol/mL in the absence of spermine. N,N-Dimethylsphingosine and N,N,N-trimethylsphingosine, which inhibit the metastatic potential of human and murine tumor cells, were weak activators of PLC delta 1. It is postulated that HPC is more effective as an antineoplastic agent than lysophospholipids because HPC is metabolized slowly, while the lysophospholipids are metabolized rapidly in vivo.
Pawelczyk
T
T
Graduate Department of Biochemistry, Brandeis University, Waltham, MA 02254.
Lowenstein
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D013096:Spermine / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D007527:Isoenzymes; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; C025059:lysophosphatidylserine; D010767:Phosphorylcholine; D013096:Spermine; C039128:miltefosine; D010738:Type C Phospholipases