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P. van Ginkel, S. Darjatmoko, L. Subramanian, D. Sareen, S. Bhattacharya, A. S. Polans; Resveratrol Inhibits Tumor Growth of Human Uveal Melanoma and Induces Apoptosis via a Mitochondrial Pathway. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1944. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma is the most common primary ocular tumor in adults. Despite advances in treatment of the primary tumor, mortality remains high due to metastatic disease which can arise years to decades after removal of the primary tumor. Therefore, the search for non-toxic therapies for long-term treatment is critical. Resveratrol, a stilbene found in many grapes and berries, has been shown to have potent anti-tumor activity in a limited number of animal studies and a large number of in vitro studies with no known toxicity at levels needed for treatment. In this study we show that resveratrol inhibits tumor growth in xenograft models of human uveal melanoma and that the drug mediates apoptosis in human uveal melanoma cell lines via the mitochondrial intrinsic apoptotic pathway.
Mice were injected subQ with 3x106 C918 or Mum2B cells and treated with resveratrol in a dose response experiment. Tumor size was recorded during the 5 week experiment. Cell viability and apoptosis of drug-treated cell lines were measured using a cell viability assay and Hoechst 333528 dye. Mitochondrial membrane potential was measured by the fluorescence dye JC-1. Cytochrome c and Smac/Diablo release into the cytoplasm as well as Bax translocation to the mitochondria were measured by Western analysis. Caspase 9 and 3 activation were measured using fluorigenic substrates.
Oral delivery of resveratrol results in a 50% reduction in tumor growth as compared to vehicle-treated mice. In addition, peritumor injection of the drug resulted in regression of the tumor. In uveal melanoma cell lines, resveratrol causes loss of cell viability and apoptosis. The drug mediates a loss of mitochondrial membrane potential, release of cytochrome c and Smac/Diablo and translocation of Bax. In addition, caspases 9 and 3 are activated.
Resveratrol is a potent, non-toxic inhibitor of uveal melanoma tumor growth. Elevated levels of the drug result in tumor regression and cell death which is corroborated by our in vitro findings. These studies suggest that the drug induces apoptosis in uveal melanoma cells by directly targeting the mitochondria, resulting in activation of the intrinsic apoptotic pathway.
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