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.

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-beta (PLC-beta) at all concentrations tested; it enhanced the activity of PI-PLC-gamma and PI-PLC-delta at low concentrations (10 microM), 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 microM) but had little effect on PI 4-kinase activity (inhibition of 13% at 150 microM). C4-PI inhibited the proliferation of MCF-7 and MDA-MB-468 cell lines with IC(50) values of 12 and 18 microM. 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.

• Authors: W Lin, L W Leung, Y S Bae, R Bittman, G Arthur
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 57 Issue 10 Pg. 1153-8 (May 15 1999) ISSN: 0006-2952 [Print] England
• PMID: 11230803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organophosphonates
• Phosphatidylinositols
• inositol 4-(hexadecyloxy)-3-methoxybutanephosphonate
• Water
• Inositol
• Type C Phospholipases
• Phosphoinositide Phospholipase C
• Phosphatidylinositol Diacylglycerol-Lyase

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (metabolism, pathology)
• Cell Line
• Epithelial Cells (drug effects, metabolism)
• Humans
• Inositol (analogs & derivatives, metabolism, pharmacology)
• Organophosphonates (chemistry)
• Phosphatidylinositol Diacylglycerol-Lyase
• Phosphatidylinositols (metabolism)
• Phosphoinositide Phospholipase C
• Solubility
• Tumor Cells, Cultured
• Type C Phospholipases (drug effects, metabolism)
• Water (chemistry)