Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction

Paul R. Van Ginkel, Soesiawati R. Darjatmoko, Dhruv Sareen, Lalita Subramanian, Saswati Bhattacharya, Mary J. Lindstrom, Daniel Albert, Arthur S. Polans

Research output: Contribution to journalArticle

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Abstract

Purpose. 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. Conclusion These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mito-chondrial 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.

Original languageEnglish (US)
Pages (from-to)1299-1306
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume49
Issue number4
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

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Growth
Neoplasms
Mitochondrial Membrane Potential
Pharmaceutical Preparations
Biological Availability
Oral Administration
Cell Survival
Animal Models
resveratrol
Uveal melanoma
Apoptosis
Injections
Therapeutics
Caspases
Cytochromes c
Caspase 3
Mitochondria
Cell Death
Coloring Agents
Fluorescence

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Van Ginkel, P. R., Darjatmoko, S. R., Sareen, D., Subramanian, L., Bhattacharya, S., Lindstrom, M. J., ... Polans, A. S. (2008). Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction. Investigative Ophthalmology and Visual Science, 49(4), 1299-1306. https://doi.org/10.1167/iovs.07-1233

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction. / Van Ginkel, Paul R.; Darjatmoko, Soesiawati R.; Sareen, Dhruv; Subramanian, Lalita; Bhattacharya, Saswati; Lindstrom, Mary J.; Albert, Daniel; Polans, Arthur S.

In: Investigative Ophthalmology and Visual Science, Vol. 49, No. 4, 01.04.2008, p. 1299-1306.

Research output: Contribution to journalArticle

Van Ginkel, PR, Darjatmoko, SR, Sareen, D, Subramanian, L, Bhattacharya, S, Lindstrom, MJ, Albert, D & Polans, AS 2008, 'Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction', Investigative Ophthalmology and Visual Science, vol. 49, no. 4, pp. 1299-1306. https://doi.org/10.1167/iovs.07-1233
Van Ginkel PR, Darjatmoko SR, Sareen D, Subramanian L, Bhattacharya S, Lindstrom MJ et al. Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction. Investigative Ophthalmology and Visual Science. 2008 Apr 1;49(4):1299-1306. https://doi.org/10.1167/iovs.07-1233
Van Ginkel, Paul R. ; Darjatmoko, Soesiawati R. ; Sareen, Dhruv ; Subramanian, Lalita ; Bhattacharya, Saswati ; Lindstrom, Mary J. ; Albert, Daniel ; Polans, Arthur S. / Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction. In: Investigative Ophthalmology and Visual Science. 2008 ; Vol. 49, No. 4. pp. 1299-1306.
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