VERAPAMIL INHIBITS TO DIFFERENT EXTENTS AGONIST-INDUCED CA2-CELLS ANDIN-VITRO TUMOR-CELL GROWTH( TRANSIENTS IN HUMAN TUMOR)

Platelet agonists are known to contribute to the regulation of cytopla smic Ca2+ levels in tumor cells and this property could be relevant in the stimulation of cell proliferation. In the present study we invest igated the ability of ADP, collagen and thrombin to increase cytoplasm ic Ca2+ levels in different human tumor cell lines (mesothelioma, DND- 1A melanoma, HeLa uterine carcinoma) and we analyzed the effect of the calcium channel blocker verapamil on Ca2+ fluxes and on in vitro tumo r cell growth, ADP was able to induce a transient increase in the cyto plasmic Ca2+ concentration in tumor cells from all lines; collagen sho wed this effect in mesothelioma cells and in HeLa cells, and thrombin was effective only in mesothelioma cells. Verapamil inhibited Ca2+ flu xes induced by the effective agonists in a dose-dependent manner. Valu es of IC50 for inhibition of ADP-induced Ca2+ transients were 63.5 mu M in mesothelioma cells, 97.3 mu M in DND-1A cells and 93.5 mu M in He La cells, while those for inhibition of collagen-induced Ca2+ movement s were slightly higher (170.2 mu M in mesothelioma cells and 112.3 mu M in HeLa cells) and the value of IC50 for inhibition of thrombin-indu ced Ca2+ fluxes (evaluated only in mesothelioma cells) was lower (22.5 mu M). The drug dose-dependently also inhibited the in vitro growth o f tumor cells: values of IC50 for growth inhibition were 21.8 mu M in mesothelioma cells, 9.1 mu M in DND-1A cells and 6.4 mu M in HeLa cell s, suggesting that the antiproliferative activity of verapamil was par tly Ca2+-independent. These data may be of interest to elucidate the m echanisms of the two-way interactions of tumors with the hemostatic sy stem and may help to identify new pharmacologic strategies for their c ontrol.