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Effects of a water-soluble antitumor ether phosphonoinositide, D-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), on inositol lipid metabolism in breast epithelial cancer cell lines

Title
Effects of a water-soluble antitumor ether phosphonoinositide, D-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), on inositol lipid metabolism in breast epithelial cancer cell lines
Authors
Lin W.Leung L.W.Bae Y.S.Bittman R.Arthur G.
Ewha Authors
배윤수
SCOPUS Author ID
배윤수scopus
Issue Date
1999
Journal Title
Biochemical Pharmacology
ISSN
0006-2952JCR Link
Citation
vol. 57, no. 10, pp. 1153 - 1158
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
We have demonstrated previously that d-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), an isosteric phosphonate analog of phosphatidylinositol developed to inhibit inositol lipid metabolism, was unable to inhibit phosphatidylinositol (PI) 3-kinase activity. We now report the effects of the compound on other aspects of inositol metabolism. We demonstrated that C4-PI inhibits the activity of purified recombinant PI-phospholipase C-β (PLC-β) at all concentrations tested; it enhanced the activity of PI-PLC-γ and PI-PLC-δ at low concentrations (10 μM), while severely inhibiting their activities at higher concentrations. In the breast cancer cell lines MCF-7 (estrogen receptor positive) and MDA-MB-468 (estrogen receptor negative), C4-PI had no effect on the uptake of d-myo-inositol but severely inhibited its incorporation into PI. In spite of the drastic decrease in PI synthesis, C4-PI did not affect the levels of inositol incorporated into phosphatidylinositol 4,5-bisphosphate (PIP2) in the cells. In vitro assays showed that C4-PI inhibited PI synthase activity (inhibition of 35% at 50 μM) but had little effect on PI 4-kinase activity (inhibition of 13% at 150 μM). C4-PI inhibited the proliferation of MCF-7 and MDA-MB-468 cell lines with ic50 values of 12 and 18 μM. Taken together, the results suggest that the accumulation of [3H]inositol in PIP2 in cells incubated with C4-PI may be due to the inhibition of PIP2 hydrolysis in the cells with no effect on its synthesis. The role of these C4-PI-induced effects in the mechanism of growth inhibition by C4-PI remains to be established. Copyright (C) 1999 Elsevier Science Inc.
DOI
10.1016/S0006-2952(99)00019-2
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