Effect of calcium and calcium antagonists on 45Ca influx and cellular growth of human prostatic tumor cells.
Calcium and calmodulin play significant roles in DNA synthesis and cell proliferation. In this work the effects of verapamil, trifluoperazine, and tamoxifen on 45Ca uptake and cell growth in human prostatic tumor cells (DU 145) and human fibroblast cells (1 BR) were studied. Although the maximum proliferation was achieved at a concentration of around 2 mM CaCl2 in both DU 145 and 1 BR, growth of DU 145 cells was considerably greater than 1 BR at all calcium concentrations (0.1-4 mM). Calcium uptake experiments, using 45Ca, revealed that the unstimulated 45Ca uptake in 1 BR fibroblasts was 4-5 times higher than in DU 145 cancer cells. Depolarization with high extracellular K caused a 2-3-fold increase in 45Ca influx in 1 BR but only 25-55% increase in DU 145 cells. Verapamil caused a significant inhibition of cell growth with an IC50 value of 55 microM. Verapamil paradoxically increased 45Ca uptake in both unstimulated and K-stimulated DU 145 cells. Whereas unstimulated 45Ca uptake could be blocked by very low concentrations of lathanum (10 microM), much higher concentrations (1-10 mM) were required to completely block uptake in K-depolarized cells. Both trifluoperazine and tamoxifen also inhibited cell proliferation with an IC50 concentration of approximately 5 microM. These drugs, had, however, no effect on 45Ca uptake either in unstimulated or depolarized cells. The results suggest that voltage-gated calcium channels exist in both DU 145 cancer cells and fibroblasts. However, verapamil, in contrast to 1 BR, failed to block these channels in DU 145 cells. The mechanism of antiproliferative action of verapamil may be related to the observed, although paradoxical, increase in cellular calcium. The effect of trifluoperazine and tamoxifen does not involve changes in transmembrane calcium movements but could be mediated by their inhibition of calmodulin-mediated reactions within the cell.
Batra
S
S
Department of Obstetrics and Gynecology, University of Lund, Sweden.
Popper
L D
LD
Hartley-Asp
B
B
D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D002132:Calcium Radioisotopes; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D011188:Potassium / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D002147:Calmodulin; D013629:Tamoxifen; D014268:Trifluoperazine; D007811:Lanthanum; D014700:Verapamil; D011188:Potassium; D002118:Calcium