QUERCETIN DOWN-REGULATES SIGNAL BREAST-CARCINOMA TRANSDUCTION IN HUMAN-CELLS

Signal transduction activity was markedly elevated in cancer cells as shown by the increased activity of enzymes utilizing 1-phosphatidylino sitol, PI (PI 4-kinase and PI-4-phosphate 5-kinase) for the production of the second messenger inositol 1,4,5-trisphosphate, IP3, in rat hep atomas (Cancer Res. 54:2611; 5574, 1994) and in human ovarian and brea st carcinoma cells (Life Sci. 55:1487, 1994). Quercetin, a flavonoid, in human breast carcinoma MDA-MB-435 cells produced growth inhibition (IC50 = 55 mu M) and cytotoxicity (LC(50) = 26 mu M). Quercetin inhibi ted PI kinase activity in extracts of breast carcinoma cells (IC50 = 6 mu M) and in cultured cells (IC50 = 10 mu M) with a minor inhibition of PIP kinase activity. IP3 concentration decreased in parallel with P I kinase activity. In time sequence studies quercetin in breast carcin oma cells brought down PI kinase and IP3 concentration in 60 min to 5 and 6%, respectively; PIP kinase activity was at 63% of controls. The results demonstrate for the first time in proliferating human breast c arcinoma cells a reduction by quercetin of the increased capacity for signal transduction, thus providing a novel and sensitive target in ca ncer cells. (C) 1995 Academic Press, Inc.