Sigma-1 and Sigma-2 receptor ligands induce apoptosis and autophagy but have opposite effect on cell proliferation in uveal melanoma
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Lucia Longhitano1, Carlo Castruccio Castracani1, Daniele Tibullo1, Roberto Avola1, Maria Viola1, Giuliano Russo1, Orazio Prezzavento4, Agostino Marrazzo4, Emanuele Amata4, Michele Reibaldi2, Antonio Longo2, Andrea Russo2, Nunziatina Laura Parrinello3 and Giovanni Li Volti1,5
1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
2Department of Ophthalmology, University of Catania, Catania, Italy
3Regional Reference Center for Rare Diseases, Clinical Division of Hematology and Transplantation, PO Ferrarotto Hospital, Azienda Ospedaliera-Universitaria Policlinico-Vittorio Emanuele, Via Citelli, Catania, Italy
4Department of Drug Sciences, University of Catania, Catania, Italy
5Euromediterranean Institute of Science and Technology, Palermo, Italy
Giovanni Li Volti, email: firstname.lastname@example.org
Keywords: uveal melanoma, sigma receptors, apoptosis, autophagy, (+)-pentazocine
Received: June 16, 2017 Accepted: July 13, 2017 Published: July 25, 2017
Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200–1500 new cases occurring per year in the United States. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs and no clinically significant chemotherapeutic protocol is so far available. The aim of the present study was to test the effect of various σ1 and σ2 receptor ligands as a possible pharmacological strategy for this rare tumor. Human uveal melanoma cells (92.1) were treated with various concentrations of different σ2 ligands (haloperidol and haloperidol metabolite II) and σ1 ligand ((+)-pentazocine) at various concentrations (1, 10 and 25 μM) and time points (0, 4 h, 8 h, 24 h and 48 h). Cell proliferation and migration were evaluated respectively by continuous cell monitoring by xCELLigence analysis, clonogenic assay and wound healing. Apoptosis and autophagy were also measured by cytofluorimetric and microscopy analysis. Our results showed that σ2 receptor ligands significantly reduced cell proliferation whereas (+)-pentazocine exhibited opposite results. All tested ligands showed significant decrease in cell migration. Interestingly, both σ1 and σ2 receptor ligands showed significant increase of autophagy and apoptosis at all concentrations. Taken all together these results suggest that sigma receptors mediates opposite biological effects but they also share common pharmacological effect on apoptosis and autophagy in uveal melanoma. In conclusion, these data provide the first evidence that sigma receptors may represent a “druggable” target to develop new chemotherapic agent for uveal melanoma.
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