Tamoxifen is a clinically useful estrogen antagonist at or below 10(-6
)M concentration. However, above this concentration tamoxifen exerts n
on-ER mediated cytotoxicity. Such cytotoxic effects are lethal or subl
ethal. The lethal effects lead to cell death while the sublethal effec
ts may lead to cellular transformation and response modification parti
cipating 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 m
ight participate in the process of carcinogenesis and/or tumor promoti
on. Tamoxifen may cause tumor stimulation due to deregulation of [Ca2](i) or its consequences such as activity of protein kinase C, calmodu
lin and related protein kinases. Precise understanding of such mechani
sm is important for avoiding tamoxifen induced tumor resistance or tum
or stimulation. The deregulation of [Ca2+](i) was studied on fluo-3/AM
loaded MCF-7 human breast cancer cells following acute and chronic tr
eatment 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 i
n [Ca2+](i) without any signs of cytotoxicity. The present data clearl
y demonstrate a tamoxifen-induced increase in [Ca2+](i) and cell death
only at the concentration-range in which non-E R mediated cytotoxicit
y is reported.