Ca2+-sensing receptors (CaSR) are G-protein coupled receptors activated by elevated concentrations of extracellular Ca2+. Cinacalcet, a positive allosteric CaSR modulator, is used as a calcimimetic to inhibit parathyroid hormone release and thus lower serum Ca2+ in hypercalcemic patients. There is a recent trend of repurposing cinacalcet in multiple applications such as anti-cancer actions, treatment of diarrhea and prevention of kidney cyst formation. In this study we investigated whether cinacalcet inhibited proliferation of endothelial cells (EC). Inhibition of EC proliferation offers an anti-angiogenesis mechanism in suppressing tumor growth. Cinacalcet at >/=18 µM caused mitochondrial membrane depolarization, suppressed proliferation and induced apoptosis in mouse bEND.3 EC. In 2 mM Ca2+-containing bath solution, cinacalcet (>/=18 µM) caused an initial rise in [Ca2+]i followed by fura-2 leakage. Similar results were obtained in Ca2+-free or 4 mM Ca2+-containing bath solution. Cinacalcet-elicited Ca2+ signal was unaffected by NPS 2143, a negative allosteric modulator of CaSR. Cinacalcet also increased Ni2+ leakage and trypan blue uptake into cells. Cinacalcet-induced membrane leakiness and cytotoxicity did not appear to be related to membrane fluidity changes. These data suggest cinacalcet, in a manner independent of CaSR stimulation and membrane fluidity perturbation, caused membrane leakiness, eventually leading to inhibition of EC proliferation and EC death. Key words Ca2+-sensing receptors " Endothelium " Cinacalcet " Ca2+ " Membrane permeability.

Division of Cardiovascular Medicine Department of Internal Medicine Wan Fang Hospital Taipei Medical University Taipei Taiwan and Department of Physiology China Medical University Taichung Taiwan

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