Tamoxifen induces deregulation of [Ca2+] in human breast cancer cells.
Tamoxifen is a clinically useful estrogen antagonist at or below 10(-6) M concentration. However, above this concentration tamoxifen exerts non-ER mediated cytotoxicity. Such cytotoxic effects are lethal or sublethal. The lethal effects lead to cell death while the sublethal effects may lead to cellular transformation and response modification participating in the process of tumor resistance or even tumor stimulation. Deregulation of intracellular ionized calcium ([Ca2+]i) could lead to genomic instability and deregulation of oncogene expression which might participate in the process of carcinogenesis and/or tumor promotion. Tamoxifen may cause tumor stimulation due to deregulation of [Ca2+]i or its consequences such as activity of protein kinase C, calmodulin and related protein kinases. Precise understanding of such mechanism is important for avoiding tamoxifen induced tumor resistance or tumor stimulation. The deregulation of [Ca2+]i was studied on fluo-3/AM loaded MCF-7 human breast cancer cells following acute and chronic treatment of tamoxifen and calcium ionophore ionomycin. The elevation of [Ca2+]i preceded the death of MCF-7 cells following treatment with ionomycin as previously reported on other cells. Tamoxifen above 10(-6) M also caused an increase in [Ca2+]i preceding the death of MCF-7 cells. However, below this concentration, tamoxifen caused a decrease in [Ca2+]i without any signs of cytotoxicity. The present data clearly demonstrate a tamoxifen-induced increase in [Ca2+]i and cell death only at the concentration-range in which non-E R mediated cytotoxicity is reported.
Jain
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PT
Department of Pathology, School of Medicine, University of Maryland at Baltimore 21201, USA. PJAIN@gems.vcu.edu
Trump
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BF
D001943:Breast Neoplasms / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D013629:Tamoxifen; D002118:Calcium