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United States Department of Agriculture

Agricultural Research Service

Research Project: Chemistry of Natural Products for Nutraceutical Use, Pest Management and Crop Development

Location: Natural Products Utilization Research

Title: Trimethoxy-resveratrol and piceatannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts

Authors
item Dias, Steven -
item Li, Kun -
item Rimando, Agnes
item Dhar, Swati -
item Mizuno, Cassia
item Penman, Alan -
item Levenson, Anait -

Submitted to: The Prostate Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 30, 2013
Publication Date: May 8, 2013
Citation: Dias, S.J., Li, K., Rimando, A.M., Dhar, S., Mizuno, C.S., Penman, A.D., Levenson, A.S. 2013. Trimethoxy-resveratrol and piceatannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts. The Prostate Journal. 73:1135-1146.

Interpretive Summary: Resveratrol is a polyphenol with promising cancer chemopreventive property. We investigated some compounds having chemical structure similar to resveratrol for their effect in preventing prostate cancer. First we examined the anti-proliferative activities of the compounds in three different prostate cancer cell lines. Then we compared the effect of resveratrol and two of the most active structural derivatives (trimethoxy-resveratrol and piceatannol) in mice. The levels of compounds in serum and tumor tissues were also measured. We found that a two-week pretreatment with the compounds diminished cell colonization, reduced tumor volume and decreased tumor growth in mice. Furthermore, both trimethoxyresveratrol and piceatannol demonstrated higher potency in inhibiting tumor progression compared to resveratrol. Notably, trimethoxyresveratrol was the most active in inhibiting cell proliferation and in suppressing colony formation, and its accumulation in both serum and tumor tissues of mice was the highest. Our findings support the veiw that these compounds, particularly trimethoxyresveratrol, are promising chemopreventive agents against prostate cancer.

Technical Abstract: Resveratrol (Res) is recognized as a promising cancer chemoprevention dietary polyphenol with antioxidative, anti-inflammatory and anticancer properties. However, the role of its analogues in prostate cancer (PCa) chemoprevention is still unknown. METHODS. We synthesized natural and synthetic analogues of Res and characterized their effects on PCa cells in vitro using cell proliferation assay. Colony formation assay and in vitro validation of luciferase (Luc) activity was done for LNCaP-Luc cells that were consequently used for in vivo studies. The efficacy of Res, trimethoxy-resveratrol (3M-Res) and piceatannol (PIC) was studied in subcutaneous (s.c) model of PCa using oral gavage. Tumor progression was monitored by traditional caliper and bioluminescent imaging. The levels of cytokines in murine serum were examined by ELISA, and the levels of compounds in serum and tumor tissues were determined by gas chromatography-mass spectrometry. RESULTS. We examined the anti-proliferative activities of Res/analogues in three PCa cell lines. We further compared the chemopreventive effects of oral Res, 3M-Res and PIC in LNCaP-Luc-xenografts. We found that a two-week pretreatment with the compounds diminished cell colonization, reduced tumor volume and decreased tumor growth in xenografts. Furthermore, both 3M-Res and PIC demonstrated higher potency in inhibiting tumor progression compared to Res. Notably, 3M-Res was the most active in inhibiting cell proliferation and suppressing colony formation, and its accumulation in both serum and tumor tissues of mice was the highest. CONCLUSIONS. Our findings offer strong pre-clinical evidence to utilize dietary stilbenes, particularly 3M-Res, as novel, potent, effective and therefore promising chemopreventive agents in PCa.

Last Modified: 12/21/2014