Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues.
Phosphatidylinositol-3-kinase (PtdIns-3-kinase) is an enzyme found associated with many growth factor receptor protein tyrosine kinases and oncogene protein tyrosine kinases. PtdIns-3-kinase appears to be important for mitogenesis and the malignant transformation of cells. The antitumor ether lipid analogue, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3), was found to be an inhibitor of Swiss mouse 3T3 fibroblast and bovine brain PtdIns-3-kinases. The concentration of ET-18-OCH3 causing 50% inhibition (IC50) was 35 microM. The inhibition of PtdIns-3-kinase by ET-18-OCH3 was noncompetitive with ATP. Other antitumor ether lipid analogues also inhibited PtdIns-3-kinase. The cyclic ether lipid analogue (+/-)-2-(hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2- yl]methoxyl)phosphinyloxy,N,N,N-trimethyethaniminium hydroxide inhibited with an IC50 of 42 microM and hexadexylphosphocholine with an IC50 of 48 microM. 1-O-Octadecyl-2-O-methyl-rac-3-glycerophospho-myo- inositol was a weaker inhibitor of PtdIns-3-kinase, with an IC50 of 96 microM and was itself phosphorylated by the enzyme. Lipid extracted from cells grown with ET-18-OCH3 for 18 h showed inhibition of PtdIns-3-kinase with endogenous PtdIns as substrate, with an ET-18-OCH3 IC50 of 18 microM. ET-18-OCH3 inhibited platelet-derived growth factor-stimulated phosphatidylinositol-3-phosphate formation by v-sis NIH 3T3 cells with an IC50 of 12.5 microM. The results of the study suggest that inhibition of PtdIns-3-kinase might contribute to the antiproliferative activity of the antitumor ether lipid analogues.
Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson 85724.
M I
MI
Berggren
A
A
Gallegos
L A
LA
Dressler
E J
EJ
Modest
G
G
Powis
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000096:biosynthesis; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D010742:Phospholipid Ethers; C055525:phosphatidylinositol 3-phosphate; C026659:edelfosine; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases