The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation

SIMPLE SUMMARY: Decades of research efforts aiming to identify a new therapy for reducing mortality rates in metastatic uveal melanoma (UM) have not been successful. While ß-blockers are already used as the gold standard in other tumors, e.g., infantile haemangiomas, UM has not received much attention. In the present study, we investigated ß-blockers to demonstrate their anti-tumor potential for the treatment of UM. Of the ß-blockers tested, carvedilol was able to block tumor cell viability and the long-term survival of the cells. Considering that brachytherapy is one of the most efficient local therapies for UM, the concurrent treatment of carvedilol and irradiation was performed, which resulted in additive effects. The anti-tumor properties of ß-blockers described in this study could lead to a new co-adjuvant treatment of UM with the aim to reduce the rate of metastasis and thus mortality. ABSTRACT: Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite local tumor control, no effective therapy has been found to prevent metastasis, resulting in a high mortality rate. In the present study, we evaluated the anti-tumor potential of non-selective ß-blockers in 3D tumor spheroids grown from UM cell lines. Of the various ß-blockers tested, carvedilol and its enantiomers were most potent in decreasing the viability of Mel270 spheroids. Carvedilol at a concentration of 10–50 µM significantly elicited cytotoxicity and induced apoptosis in spheroid cells. In result, carvedilol inhibited tumor spheroid growth and compactness, and furthermore prevented the long-term survival and repopulation of spreading spheroid cells. The drug sensitivity of the different spheroids grown from Mel270, 92-1, UPMD2, or UPMM3 cell lines was dependent on 3D morphology rather than on high-risk cytogenetic profile or adrenergic receptor expression levels. In fact, the monosomy-3-containing UPMM3 cell line was most responsive to carvedilol treatment compared to the other cell lines. The concurrent treatment of UPMM3 spheroids with carvedilol and 5 or 10 Gy irradiation revealed additive cytotoxic effects that provided tumor control. Collectively, our data demonstrate the anti-tumor properties of carvedilol and its enantiomers, which may serve as candidates for the co-adjuvant therapy of UM.