INHIBITION OF THE SIGNALING ENZYME PHOSPHATIDYLINOSITOL-3-KINASE BY ANTITUMOR ETHER LIPID ANALOGS

Phosphatidylinositol-3-kinase (PtdIns-3-kinase) is an enzyme found ass ociated with many growth factor receptor protein tyrosine kinases and oncogene protein tyrosine kinases. PtdIns-3-kinase appears to be impor tant for mitogenesis and the malignant transformation of cells. The an titumor ether lipid analogue, -octadecyl-2-O-methyl-rac-glycero-3-phos phocholine (ET-18-OCH3), was found to be an inhibitor of Swiss mouse 3 T3 fibroblast and bovine brain PtdIns-3-kinases. The concentration of ET-18-OCH3 causing 50% inhibition (IC50) was 35 muM. The inhibition of PtdIns-3-kinase by ET-18-OCH3 was noncompetitive with ATP. Other anti tumor ether lipid analogues also inhibited PtdIns-3-kinase. The cyclic ether lipid analogue -decyloxy)methylfuran-2-yl]methoxyl}phosphinylox y, N,N,N-trimethyethaniminium hydroxide inhibited with an IC50 of 42 m uM and hexadexylphosphocholine with an IC50 of 48 muM. decyl-2-O-methy l-rac-3-glycerophospho-myo-inositol was a weaker inhibitor of PtdIns-3 -kinase, with an IC50 of 96 muM and was itself phosphorylated by the e nzyme. Lipid extracted from cells grown with ET-18-OCH3 for 18 h showe d inhibition of PtdIns-3-kinase with endogenous PtdIns as substrate, w ith an ET-18-OCH3 IC50 of 18 muM. ET-18-OCH3 inhibited platelet-derive d growth factor-stimulated phosphatidylinositol-3-phosphate formation by v-sis NIH 3T3 cells with an IC50 of 12.5 muM. The results of the st udy suggest that inhibition of PtdIns-3-kinase might contribute to the antiproliferative activity of the antitumor ether lipid analogues.