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 Ca ²⁺ indicator. Fendiline at concentrations between 3 and 200 μmol/l increased [Ca²⁺]_i in a concentration-dependent manner and the signal saturated at 100 μmol/l. The [Ca²⁺]_i signal was biphasic, with an initial rise and a slow decay. Ca²⁺ removal inhibited the Ca²⁺ signal by about half in peak amplitude. Adding 3 mmol/l Ca²⁺ increased [Ca²⁺]_i in cells pretreated with 100 μmol/l fendiline in Ca²⁺-free medium, suggesting that fendiline induced Ca²⁺ influx via capacitative Ca²⁺ entry. In Ca²⁺-free medium, pretreatment with 1 μmol/l thapsigargin (an endoplasmic reticulum Ca²⁺ pump inhibitor) to deplete the endoplasmic reticulum Ca²⁺ store inhibited most of the 100 μmol/l fendiline-induced internal Ca²⁺ release; and conversely, pretreatment with 100 μmol/l fendiline partly inhibited 1 μmol/l thapsigargin-induced Ca²⁺ release. This indicates that the major internal Ca²⁺ store of fendiline-induced [Ca²⁺]_i increases is located in the endoplasmic reticulum. The Ca²⁺ release induced by 100 μmol/l fendiline may be partly mediated by inositol 1,4,5-trisphosphate, because the [Ca²⁺]_i increase was inhibited by 50% by inhibiting phospholipase C with 2 μmol/l U73122. Fendiline (100 μmol/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: mobilization of intracellular Ca²⁺ and induction of cell death.