This study examined the effect of tamoxifen, an anti-breast cancer drug, on
Ca2+ handling in bladder female transitional cancer cells. Changes in cyto
solic free Ca2+ levels were recorded by using the Ca2+-sensitive dye fura-2
. In a dose-dependent manner, tamoxifen induced intracellular free Ca2+ con
centrations ([Ca2+](i)) increases between 5 and 20 muM with an EC50 of 10 m
uM. External Ca2+ removal reduced the response by 60+/-6%. Addition of 3 mM
Ca2+ caused a [Ca2+](i) increase after pretreatment with 10 muM tamoxifen
in Ca2+-free medium. In Ca2+-free medium, pretreatment with 10 muM tamoxife
n abolished the [Ca2+](i) increase induced by 1 muM thapsigargin, an endopl
asmic reticulum Ca2+ pump inhibitor. Conversely, pretreatment with 1 muM th
apsigargin prevented tamoxifen from releasing more Ca2+. Inhibition of phos
pholipase C-dependent inositol 1,4,5-tris-phosphate formation with 2 muM U7
3122 did not alter 10 muM tamoxifen-induced Ca2+ release. The [Ca2+](i) inc
rease induced by 5 muM tamoxifen was not altered by 10 muM La3+, nifedipine
, verapamil, and diltiazem. Collectively, it was found that tamoxifen incre
ased [Ca2+](i) in bladder cancer cells by releasing Ca2+ from the endoplasm
ic reticulum Ca2+ stores in a manner independent of phospholipase C activit
y, and by inducing Ca2+ entry from external medium.