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Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues.
Cancer Res. 1993 Sep 15; 53(18):4297-302.CR

Abstract

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.

Authors+Show Affiliations

Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson 85724.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8395981

Citation

Berggren, M I., et al. "Inhibition of the Signalling Enzyme Phosphatidylinositol-3-kinase By Antitumor Ether Lipid Analogues." Cancer Research, vol. 53, no. 18, 1993, pp. 4297-302.
Berggren MI, Gallegos A, Dressler LA, et al. Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues. Cancer Res. 1993;53(18):4297-302.
Berggren, M. I., Gallegos, A., Dressler, L. A., Modest, E. J., & Powis, G. (1993). Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues. Cancer Research, 53(18), 4297-302.
Berggren MI, et al. Inhibition of the Signalling Enzyme Phosphatidylinositol-3-kinase By Antitumor Ether Lipid Analogues. Cancer Res. 1993 Sep 15;53(18):4297-302. PubMed PMID: 8395981.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the signalling enzyme phosphatidylinositol-3-kinase by antitumor ether lipid analogues. AU - Berggren,M I, AU - Gallegos,A, AU - Dressler,L A, AU - Modest,E J, AU - Powis,G, PY - 1993/9/15/pubmed PY - 1993/9/15/medline PY - 1993/9/15/entrez SP - 4297 EP - 302 JF - Cancer research JO - Cancer Res VL - 53 IS - 18 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/8395981/Inhibition_of_the_signalling_enzyme_phosphatidylinositol_3_kinase_by_antitumor_ether_lipid_analogues_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=8395981 DB - PRIME DP - Unbound Medicine ER -