Tamoxifen and genistein synergistically down-regulate signal transduction and proliferation in estrogen receptor-negative human breast carcinoma MDA-MB-435 cells.
OBJECTIVE
Tamoxifen and genistein were tested for synergism in estrogen receptor- negative human breast carcinoma MDA-MB-435 cells because the two compounds decrease signal transduction activity through different biochemical mechanisms and arrest the cell cycle at different phases.


METHODS
The combination effect of tamoxifen and genistein on signal transduction was determined by measuring IP3 concentrations and on cell proliferation and colony formation by growth inhibition assay and clonogenic assay.


RESULTS
In growth inhibition assays, for tamoxifen and genistein in the carcinoma cells the IC50s were (mean +/- SE) 17 +/- 0.9 and 27 +/- 1.6 microM; in clonogenic assays the LC50s were 0.9 +/- 0.4 and 12.5 +/- 1.1 microM, respectively. When tamoxifen and genistein were simultaneously added to the cells, synergism was observed in growth inhibition, in cytotoxicity and in the reduction of inositol 1,4,5-trisphosphate concentration.


CONCLUSIONS
The synergistic down-regulation of signal transduction by tamoxifen and genistein may explain, in part at least, the synergistic antiproliferative and cytotoxic actions of the two compounds. The synergism of tamoxifen and genistein may be of interest in the clinical treatment of breast carcinoma.
Shen
F
F
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5119, USA.
Xue
X
X
Weber
G
G
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000032:analysis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D013629:Tamoxifen; D015544:Inositol 1,4,5-Trisphosphate; D019833:Genistein