Tamoxifen downregulates signal transduction and is synergistic with tiazofurin in human breast carcinoma MDA-MB-435 cells.

Breast carcinoma is a leading cause of cancer death in women in the US. Tamoxifen (TAM), an antiestrogen, is used as a chemopreventive and chemotherapeutic compound against human breast carcinoma. Tiazofurin (TR), an oncolytic C-nucleoside, inhibits IMP dehydrogenase activity, decreases cellular GTP pools, and downregulates ras gene expression. MDA-MB-435 cells are estrogen receptor negative human breast carcinoma cells that have elevated signal transduction activity. Because TR and TAM decrease signal transduction enzyme activity and inositol 1,4,5-trisphosphate (IP3) concentration via different mechanisms, we tested the hypothesis that the two compounds may be synergistic in human breast carcinoma cells. In MDA-MB-435 cells in growth inhibition assay, the IC50s for TR and TAM were (mean +/- SE) 17 +/- 1.2 and 12 +/- 1.1 microM; in clonogenic assays they were 4 +/- 0.3 and 0.7 +/- 0.3 microM, respectively. When TR was added to MDA-MB-435 cells, followed 12 h later by TAM, synergism was observed in growth inhibition and clonogenic assays and in the reduction of IP3 concentration. The latter may explain, at least in part, the synergistic action of TR and TAM in these cells. The synergistic action of TR and TAM may have implication in the clinical treatment of human breast carcinoma.