Mechanisms of the action of zoledronic acid on human MG-63 osteosarcoma cells.

The aim of our study was to analyze the action of zoledronic acid on MG-63 human osteosarcoma cells. The proliferation of MG-63 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner (10-250 microM). Zoledronic acid did not produce evidence of MG-63 cell death when administered at 100 mM for 48 hours, but only after exposure of 96 hours. Zoledronic acid (100 microM) increased the distribution of MG-63 cells in G0/G1 phase, however, it did not increase the adriamycin-induced apoptosis. In addition, zoledronic acid action was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), but not by farnesyl pyrophosphate (FPP). Furthermore, zoledronic acid resulted in the attenuation of the prenylated form of Ras. Zoledronic acid and EDTA increased fluorescence of Fluo-3 loaded MG-63 cells in a similar pattern. This increase was owing to the release of Ca2+ from intracellular stores since zoledronic acid failed to reveal such a change to intracellular Ca2+ when cells were previously treated with 1 mM caffeine. Moreover, zoledronic acid significantly decreased the expression of estrogen receptor alpha (ERalpha) whereas it did not change significantly the expression of estrogen receptor beta (ERbeta) in MG-63 cells. These data suggest that zoledronic acid can control the proliferation and the differentiation of osteosarcoma-like cells.

Calcium dobesilate and transmembrane potential in canine cardiac cells. A preliminary study.

The electropharmacological effects of calcium 2,5-dihydroxybenzene sulfonate (calcium dobesilate, Doxium) were studied by means of intracellular microelectrode technique in order to measure the changes in action potentials (A.ps.) in dog isolated cardiac Purkinje fibers and the adjacent ventricular tissue superfused with Tyrode's solution. The addition of 25 mmol/l of calcium dobesilate to the superfusate suppressed automaticity in spontaneously functioning preparation. The frequency of the action potentials was decreased and their duration increased with elevation and prolongation of their plateau phase. These effects were produced in both Purkinje and adjacent ventricular fibers and they were reversed by washing out with Tyrode's solution. Addition of calcium (25 mmol/l) restored automaticity in preparation in which spontaneous activity had been previously arrested by tetrodotoxin (10(-4) mol/l). Calcium dobesilate-induced action potentials were slow i.e. with low dV/dtmax and were abolished by verapamil (10(-5) mol/l). Calcium dobesilate increased the contractile force in both normally working and tetrodotoxin-arrested preparations. These findings suggest that calcium dobesilate acts on the myocardial cell by promoting transmembrane calcium influx during the plateau phase through activation of the slow inward calcium current.