Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.
OBJECTIVE
To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma.


METHODS
The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases.


RESULTS
Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3.


CONCLUSIONS
These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.
van Ginkel
Paul R
PR
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.
Darjatmoko
Soesiawati R
SR
Sareen
Dhruv
D
Subramanian
Lalita
L
Bhattacharya
Saswati
S
Lindstrom
Mary J
MJ
Albert
Daniel M
DM
Polans
Arthur S
AS
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001682:Biological Availability; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D013267:Stilbenes; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D000077185:Resveratrol