PLATELET AGONISTS INDUCE CA2(-CELLS BY OPENING DISTINCT RECEPTOR-OPERATED CHANNELS - AN EFFECT UNRELATED TO THE PRESENCE OF CLASSICAL MULTIDRUG-RESISTANCE PHENOTYPE() TRANSIENTS IN TUMOR)

Background - Modulation of the cytoplasmic calcium concentration is a mechanism of signal transduction regulating several biological phenome na and may also play a role in the stimulation of cell, proliferation. In the present study we have investigated the effect of different pla telet agonists on cytoplasmic Ca2+ levels in tumor cells with or witho ut the multi-drug resistance (MDR) phenotype and the effects of verapa mil on agonist induced Ca2+ transients and on in-vitro tumor cell grow th, Methods - LoVo cells and doxorubicin-resistant LoVoDx cells, deriv ed from a human colon adenocarcinoma, were cultured in vitro using sta ndard methods. Cytoplasmic Ca2+ levels in aequorin-loaded tumor cells were determined in a Platelet Ionized Calcium Aggregometer. Results - ADP, GRGDS, PAF, collagen and thrombin were able to induce Ca2+ transi ents in both cell lines, while U46619, a thromboxane A(2) mimetic agen t, PDGF and carbachol were not. Tumor cells of both cell lines became refractory to thrombin after the first addition, but remained sensitiv e to the other inducers. Furthermore, the calcium channel blocker vera pamil significantly inhibited thrombin-induced Ca2+ fluxes in both LoV o cells and LoVoDx cells and had no significant effect on Ca2+ movemen ts induced by the other agonists, Finally, the drug inhibited the in-v itro growth of both cell lines in a dose-dependent manner, with an eff ect more evident in resistant cells, Conclusions. - These data may hel p to explain the ability of verapamil to reverse the MDR phenotype and may contribute to identifying new mechanisms for the two-way interact ion of tumors with the hemostatic system.