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ORIGINAL RESEARCH ARTICLE

Sulforaphane Retards the Growth of Human PC-3 Xenografts and Inhibits HDAC Activity in Human Subjects

Melinda C. Myzak^*,, Philip Tong^*,, Wan-Mohaiza Dashwood^*, Roderick H. Dashwood^*, and Emily Ho^*,,1

^* Linus Pauling Institute, Molecular and Cellular Biology Program, Department of Environmental and Molecular Toxicology, and Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, Oregon 97331

To whom requests for reprints should be addressed at ¹ Oregon State University, 108 Milam Hall, Corvallis, OR, 97331. E-mail: Emily.Ho{at}oregonstate.edu

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables such as broccoli. This anticarcinogen was first identified as a potent inducer of Phase 2 enzymes, but evidence is mounting that SFN acts through other cancer chemopreventive mechanisms. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells and prostate epithelial cells, namely the inhibition of histone deacetylase (HDAC). In the present investigation, we sought to test whether SFN also might inhibit HDAC activity in vivo. When consumed in the diet at an average daily dose of 7.5 µmol per animal for 21 days, SFN suppressed the growth of human PC-3 prostate cancer cells by 40% in male nude mice. There was a significant decrease in HDAC activity in the xenografts, as well as in the prostates and mononuclear blood cells (MBC), of mice treated with SFN, compared to controls. There also was a trend towards increased global histone acetylation in the xenografts, prostates, and MBC. In human subjects, a single dose of 68 g BroccoSprouts inhibited HDAC activity significantly in peripheral blood mononuclear cells (PBMC) 3 and 6 hrs following consumption. These findings provide evidence that one mechanism through which SFN acts as a cancer chemopreventive agent in vivo is through the inhibition of HDAC activity. Moreover, the data suggest that HDAC activity in PBMC may be used as a biomarker for assessing exposure to novel dietary HDAC inhibitors in human subjects.

Key Words: prostate cancer • histone deacetylase inhibitor • sulforaphane mechanisms of prevention • diet and cancer