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Eva Jin, Prisca Bustamante, Denise Miyamoto, Jade Lasiste, Alicia Alejandra Goyeneche, Miguel N Burnier, Julia Burnier; Beta-blocker: a potential adjuvant therapy for Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):744. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma (UM) is the most common intraocular tumor in adults and the most frequent non-cutaneous form of melanoma. Despite current local treatments, 50% of UM patients develop metastasis, thus new adjuvant therapies are crucial for disease control. β-blockers have been previously tested and show anti-tumor efficacy in cutaneous melanoma (CM) by reducing tumorgenicity and angiogenesis Thus, the objective of this study is to evaluate the expression of β-blocker receptors in UM cell lines and tissue, and determine the activity of propranolol, a non-specific β-blocker, against human UM and CM cells in vitro.
Automated immunocytochemistry was performed to determine expression of Beta adrenoreceptor-1 (β1AR) and β2AR in human UM and CM cells (primary and metastatic), and in 33 enucleated UM cases. β-AR expression was evaluated using an additive score combining intensity and extension of positivity. Then, human UM (MEL270, OMM2.5, MP41, MP46) and CM (WM115, WM266.4) cell lines were treated with propranolol to determine the functional effects of beta-blocker therapy in melanoma cells. Cytotoxicity, cell migration, and apoptosis were determined after propranolol treatment. Finally, to determine the effect of propranolol on angiogenesis, VEGF levels in the cell culture supernatant of UM and CM cells were measured before and after treatment.
Immunohistochemical expression of β1 and β2-AR was positive in primary and metastatic UM cell lines as well as in all enucleated UM cases (n=33). Our results showed a significantly higher expression in epithelioid than spindle-cell tumors (P = 0.00018), and higher levels of expression was found in cells showing particularly aggressive phenotypes. Treatment with propranolol resulted in decreased cell migration, decreased cell viability, and greater apoptosis after 24h in a dose-dependent manner. VEGF levels in supernatant were also significantly reduced after 24h-treatment with propranolol (40uM) in comparison with no treatment (p<0.05).
To the best of our knowledge, this is the first analysis of propranolol as an anti-tumor agent in UM and the first report of β-adrenoceptor expression in human UM. Our results suggest that propranolol should be evaluated as an adjuvant therapy in UM. Further studies are needed to elucidate the role of β-blockers in UM.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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