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Inhibition of growth factor-dependent inositol phosphate Ca2+ signaling by antitumor ether lipid analogues.
Cancer Res. 1990 Aug 01; 50(15):4458-63.CR

Abstract

Cytotoxic ether lipid analogues have been studied for their ability to inhibit growth factor-dependent [Ca2+]i signaling in Swiss 3T3 fibroblasts. 1-Octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) inhibited 45Ca2+ uptake and inositol(1,4,5)trisphosphate-induced 45Ca2+ release in saponin permeabilized cells with concentration producing 50% inhibition values of 55 and 360 microM, respectively. When cells were exposed to ET-18-OCH3 for 18 h before permeabilization there was selective inhibition of inositol(1,4,5)trisphosphate-induced 45Ca2+ release with a concentration producing 50% inhibition value of 20 microM, but no effect on 45Ca2+ uptake, or on 45Ca2+ release by arachidonic acid. The concentration of ET-18-OCH3 with continuous exposure to inhibit cell growth 50% was 19 microM. The ether lipid analogues 1-hexadecylthio-2-ethyl-rac-glycero-3- phosphocholine and 1-S-octadecyl-2-O-methylthiopropyl-3-N,N-dimethyl-gamma-hydroxy pro pyl ammonium iodide had effects similar to those of ET-18-OCH3 but the noncytotoxic analogue 1-alkyl-2-hydroxy-sn-glycero-3- phosphocholine was without effect. Exposure of cells to 10 microM ET-18-OCH3 produced 81% inhibition of platelet-derived growth factor-stimulated inositol phosphate formation and 66% inhibition of fluoroaluminate anion-stimulated inositol phosphate formation. Addition of ET-18-OCH3 to cells in medium with 10% fetal calf serum gave a transient increase in [Ca2+]i without causing an increase in resting [Ca2+]i, while the addition of ET-18-OCH3 to cells in medium without serum gave a sustained increase in resting [Ca2+]i. Cells exposed to 5 microM ET-18-OCH3 for 18 h showed no increase in resting [Ca2+]i but there was 95% inhibition of the [Ca2+]i response to platelet-derived growth factor, 63% inhibition of the response to bradykinin, and 55% inhibition of the response to vasopressin. The block by ether lipid analogues of inositol phosphate-mediated [Ca2+]i signaling suggests a mechanism for preventing the action of growth factors that could contribute to the inhibition of cell proliferation by the agents.

Authors+Show Affiliations

Department of Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.No affiliation info availableNo 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

2369723

Citation

Seewald, M J., et al. "Inhibition of Growth Factor-dependent Inositol Phosphate Ca2+ Signaling By Antitumor Ether Lipid Analogues." Cancer Research, vol. 50, no. 15, 1990, pp. 4458-63.
Seewald MJ, Olsen RA, Sehgal I, et al. Inhibition of growth factor-dependent inositol phosphate Ca2+ signaling by antitumor ether lipid analogues. Cancer Res. 1990;50(15):4458-63.
Seewald, M. J., Olsen, R. A., Sehgal, I., Melder, D. C., Modest, E. J., & Powis, G. (1990). Inhibition of growth factor-dependent inositol phosphate Ca2+ signaling by antitumor ether lipid analogues. Cancer Research, 50(15), 4458-63.
Seewald MJ, et al. Inhibition of Growth Factor-dependent Inositol Phosphate Ca2+ Signaling By Antitumor Ether Lipid Analogues. Cancer Res. 1990 Aug 1;50(15):4458-63. PubMed PMID: 2369723.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of growth factor-dependent inositol phosphate Ca2+ signaling by antitumor ether lipid analogues. AU - Seewald,M J, AU - Olsen,R A, AU - Sehgal,I, AU - Melder,D C, AU - Modest,E J, AU - Powis,G, PY - 1990/8/1/pubmed PY - 1990/8/1/medline PY - 1990/8/1/entrez SP - 4458 EP - 63 JF - Cancer research JO - Cancer Res VL - 50 IS - 15 N2 - Cytotoxic ether lipid analogues have been studied for their ability to inhibit growth factor-dependent [Ca2+]i signaling in Swiss 3T3 fibroblasts. 1-Octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) inhibited 45Ca2+ uptake and inositol(1,4,5)trisphosphate-induced 45Ca2+ release in saponin permeabilized cells with concentration producing 50% inhibition values of 55 and 360 microM, respectively. When cells were exposed to ET-18-OCH3 for 18 h before permeabilization there was selective inhibition of inositol(1,4,5)trisphosphate-induced 45Ca2+ release with a concentration producing 50% inhibition value of 20 microM, but no effect on 45Ca2+ uptake, or on 45Ca2+ release by arachidonic acid. The concentration of ET-18-OCH3 with continuous exposure to inhibit cell growth 50% was 19 microM. The ether lipid analogues 1-hexadecylthio-2-ethyl-rac-glycero-3- phosphocholine and 1-S-octadecyl-2-O-methylthiopropyl-3-N,N-dimethyl-gamma-hydroxy pro pyl ammonium iodide had effects similar to those of ET-18-OCH3 but the noncytotoxic analogue 1-alkyl-2-hydroxy-sn-glycero-3- phosphocholine was without effect. Exposure of cells to 10 microM ET-18-OCH3 produced 81% inhibition of platelet-derived growth factor-stimulated inositol phosphate formation and 66% inhibition of fluoroaluminate anion-stimulated inositol phosphate formation. Addition of ET-18-OCH3 to cells in medium with 10% fetal calf serum gave a transient increase in [Ca2+]i without causing an increase in resting [Ca2+]i, while the addition of ET-18-OCH3 to cells in medium without serum gave a sustained increase in resting [Ca2+]i. Cells exposed to 5 microM ET-18-OCH3 for 18 h showed no increase in resting [Ca2+]i but there was 95% inhibition of the [Ca2+]i response to platelet-derived growth factor, 63% inhibition of the response to bradykinin, and 55% inhibition of the response to vasopressin. The block by ether lipid analogues of inositol phosphate-mediated [Ca2+]i signaling suggests a mechanism for preventing the action of growth factors that could contribute to the inhibition of cell proliferation by the agents. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/2369723/Inhibition_of_growth_factor_dependent_inositol_phosphate_Ca2+_signaling_by_antitumor_ether_lipid_analogues_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=2369723 DB - PRIME DP - Unbound Medicine ER -