Tamoxifen and genistein synergistically down-regulate signal transduction and proliferation in estrogen receptor-negative human breast carcinoma MDA-MB-435 cells

Purpose. Tamoxifen and genistein were tested for synergism in estrogen rece ptor- negative human breast carcinoma MDA-MB-435 cells because the two comp ounds decrease signal transduction activity through different biochemical m echanisms and arrest the cell cycle at different phases. Materials and Meth ods. The combination effect of tamoxifen and genistein on signal transducti on was determined by measuring IP3 concentrations and on cell proliferation anal colony formation by growth inhibition assay and clonogenic assay. Res ults. In growth inhibition assays, for tamoxifen and genistein in the carci noma cells the IC(50)s were (mean +/- SE) 17 +/- 0.9 and 27 +/- 1.6 mu M; i n clonogenic assays the LC(50)s were 0.9 +/- 0.4 and 12.5 +/- 1.1 mu M, res pectively. When tamoxifen and genistein were simultaneously added to the ce lls, synergism was observed in growth inhibition, in cytotoxicity and in th e reduction of inositol 1,4,5-trisphosphate concentration. Conclusion. The synergistic down-regulation of signal transduction by tamoxifen and geniste in may explain in part at least, the synergistic antiproliferative and cyto toxic actions of the two compounds. The synergism of tamoxifen and genistei n may be of interest in the clinical treatment of breast carcinoma.