Klaus H. Baumann, Elmar Klusmeier, Isabel Eggemann, Silke Reinartz, Achim Almeroth, Mathias Kalder and Uwe Wagner

University Hospital of Gießen and Marburg, Location Marburg, Dept. of Gynecology, Gynecological Endocrinology and Oncology, 35043 Marburg, Germany.

Abstract

Activation and signalling of estrogen receptor (ER) and COX-2 represent two important pathways in breast cancer cell regulation. Activation of either pathway is associated with breast cancer cell proliferation and eventually malignant progression. Raloxifene analogue, Ly117018, a selective estrogen receptor modulator and celecoxib, a specific COX- 2 inhibitor have been shown to inhibit breast cancer cell proliferation when used alone in vitro and in vivo. In this study, the combined drug effects on hormone-dependent MCF-7 and hormone-independent MDA-MB-435 cells in vitro were evaluated. Cell proliferation assays excluded drug antagonism and revealed a moderate synergistic growth inhibitory activity of Ly117018 and celecoxib on both cell lines when combined in specific concentrations. Growth inhibition of either compound was not associated with cell cycle arrest. In MCF-7 cells, western blot analysis revealed a decreased phosphorylation of the AKT protein by either agent alone or in combination. In MDA-MB-435 cells, celecoxib alone induced an increase in AKT phosphorylation relative to total AKT protein; this effect was decreased in the presence of Ly117018. These results indicate that these two drugs are non-antagonistic; and when combined in specific concentrations, moderate synergistic antiproliferative activity of celecoxib and Ly117018 were observed in hormone-dependent MCF-7 and hormone- independent MDA-MB-435 cells associated with changes in cell cycle distribution and regulation of AKT protein and phosphorylation. These findings further support a central role of the ER- and COX-2 pathways in human breast cancer cells.