SK&F 96365 (1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl}-1H-imidazole hydrochloride) stimulates phosphoinositide hydrolysis in human U373 MG astrocytoma cells

• Published in: Biochemical pharmacology Vol. 56; no. 8; pp. 1023 - 1027
• Main Authors: ARIAS-MONTANO, J.-A, GIBSON, W. J, YOUNG, J. M
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Science 15.10.1998
• Subjects: Animals; Astrocytoma - drug therapy; Astrocytoma - metabolism; Biological and medical sciences; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - metabolism; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Guinea Pigs; HeLa Cells; Humans; Hydrolysis; Imidazoles - pharmacology; In Vitro Techniques; Medical sciences; Neurology; Phosphatidylinositols - metabolism; Radioligand Assay; Rats; Stimulation, Chemical; Tumor Cells, Cultured; Tumors of the nervous system. Phacomatoses; Cerebellum; Human; Imidazole derivatives; Nervous system diseases; Cerebral cortex; Rat; Rodentia; Central nervous system; Malignant tumor; Inositol phosphate; Malignant glioma; Vertebrata; Antifungal agent; Mammalia; Guinea pig; Animal; Malignant astrocytoma; Central nervous system disease; Established cell line; Miconazole; Tumor cell; Calcium Cations
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(98)00125-7

SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H-imi dazole hydrochloride) stimulated the accumulation of [3H]inositol monophosphates ([3H]IP1) in human U373 MG astrocytoma cells prelabelled with [3H]inositol (EC50 15 +/- 1 microM, Hill coefficient 3.8 +/- 0.4). SK&F 96365-induced accumulation of [3H]IP1 increased linearly with time, but there was no initial rapid formation of [3H]IP3. SK&F 96365 also stimulated [3H]IP1 accumulation in human HeLa cells, but only to a small extent in slices of rat cerebral cortex and guinea-pig cerebellum. SK&F 96365-induced accumulation of [3H]IP1 in U373 MG cells increased as extracellular Ca2+ was increased from nominally zero to 4 mM, but there was no evidence that SK&F 96365 induced any marked entry of Ca2+ into cells; only an inhibition of store-refilling-induced Ca2+ entry was apparent. Further, the response to SK&F 96365 was additive with that to the Ca2+ ionophore ionomycin. Depolarization of the cells with raised K+ produced only a small stimulation of phosphoinositide hydrolysis. SK&F 96365 caused the release of Ca2+ from intracellular stores in U373 MG cells (EC50 26 +/- 14 microM), but thapsigargin induced only a small accumulation of [3H]IP1. Miconazole, another N-substituted imidazole, also stimulated [3H]IP1 accumulation in U373 cells.