Dual effect of the antianginal drug fendiline on bladder female transitional carcinoma cells: Mobilization of intracellular Ca2+ and induction of cell death

The effect of fendiline, an antianginal drug, on cytosolic free Ca2+ levels ((Ca2+)(i)) in populations of bladder female transitional carcinoma (BFTC) cells was explored using fura-2 as a Ca2+ indicator. Fendiline at concentr ations between 3 and 200 mu mol/l increased [Ca2+](i) in a concentration-de pendent manner and the signal saturated at 100 mu mol/l. The (Ca2+)(i) sign al was biphasic, with an initial rise and a slow decay. Ca2+ removal inhibi ted the Ca2+ signal by about half in peak amplitude. Adding 3 mmol/l C2+ in creased (Ca2+)(i) in cells pretreated with 100 mu mol/l fendiline in Ca2+-f ree medium, suggesting that fendiline induced Ca2+ influx via capacitative Ca2+ entry. In Ca2+-free medium, pretreatment with 1 mu mol/l thapsigargin tan endoplasmic reticulum Ca2+ pump inhibitor to deplete the endoplasmic re ticulum Ca2+ store inhibited most of the 100 mu mol/l fendiline-induced int ernal Ca2+ release; and conversely, pretreatment with 100 mu mot/l fendilin e partly inhibited 1 mu mol/l thapsigargin-induced Ca2+ release. This indic ates that the major internal Ca2+ store of fendiline-induced (Ca2+)(i) incr eases is located in the endoplasmic reticulum. The Ca2+ release induced by 100 mu mol/l fendiline may be partly mediated by inositol 1,4,5-trisphospha te, because the (Ca2+)(i) increase was inhibited by 50% by inhibiting phosp holipase C with 2 mu mol/l U73122. Fendiline (100 mu mol/l) decreased cell viability by 12-44% after being added to cells for 2-30 min. Together, the findings indicate that in BFTC cells, fendiline exerts a dual effect: mobil ization of intracellular Ca2+ and induction of cell death. Copyright (C) 20 01 S. Karger AG, Basel.