Abstract
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.
Highlights
Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200–1500 new cases occurring per year in the United States [1, 2]. both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma is biologically and genetically distinct from the more common cutaneous melanoma
All tested ligands showed significant decrease in cell migration. 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 share common pharmacological effect on apoptosis and autophagy in uveal melanoma
Our results showed that all tested compounds promote apoptosis and autophagy whereas the σ1 receptor agonist (+)-pentazocine has opposite effects on cell proliferation with respect to haloperidol and haloperidol metabolite II, which possess σ1 antagonist/σ2 ligand profiles
Summary
Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200–1500 new cases occurring per year in the United States [1, 2]. both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma is biologically and genetically distinct from the more common cutaneous melanoma. Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200–1500 new cases occurring per year in the United States [1, 2]. Bioinformatics as well as other methods are regression, classification or statistical methods used in the chemical and biological sciences helping in predict variables or in understanding patterns [6,7,8] To this regard, a recent report using the L1000CDS2 web-based utility was able to predict small molecules and drugs targeting uveal melanoma gene signature [9]. A recent report using the L1000CDS2 web-based utility was able to predict small molecules and drugs targeting uveal melanoma gene signature [9] In this bioinformatics study, cinnarizine (Figure 1), an anti-histaminic drug used for motion sickness, was proposed as a promising drug for the treatment of metastatic uveal melanoma [9].
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