Broccoli compound may aid survival for high-risk prostate cancer patients

Scientists at Oregon State University and Linus Pauling Institute propose in an article published October 7 that sulforaphane, a compound found in cruciferous vegetables notably broccoli, may be useful as a chemopreventive agent for high-risk prostate cancer patients. Sulforaphane, Emily Ho and colleagues write, acts as a histone deacetylase inhibitor on prostate cancer (and colorectal cancer) cells.

Levels of sulforaphane in cruciferous vegetables including broccoli are low, of course, compared to levels of HDAC inhibitors tested in laboratory studies on cancer cells, in mice and (see below) on patients in clinical trials. Nonetheless, the authors of the current study write:

The reversible acetylation of histones is an important mechanism of gene regulation. During prostate cancer progression, specific modifications in acetylation patterns on histones are apparent. Targeting the epigenome, including the use of histone deacetylase (HDAC) inhibitors, is a novel strategy for cancer chemoprevention. Recently, drugs classified as HDAC inhibitors have shown promise in cancer clinical trials. We have previously found that sulforaphane (SFN), a compound found in cruciferous vegetables, inhibits HDAC activity in human colorectal and prostate cancer cells. Based on the similarity of SFN metabolites and other phytochemicals to known HDAC inhibitors, we previously demonstrated that sulforaphane acted as an HDAC inhibitor in the prostate, causing enhanced histone acetylation, derepression of P21 and Bax, and induction of cell cycle arrest/apoptosis, leading to cancer prevention. The ability of SFN to target aberrant acetylation patterns, in addition to effects on phase 2 enzymes, may make it an effective chemoprevention agent. These studies are important because of the potential to qualify or change recommendations for high-risk prostate cancer patients and thereby increase their survival through simple dietary choices incorporating easily accessible foods into their diets. These studies also will provide a strong scientific foundation for future large-scale human clinical intervention studies.

Other studies have found that men diagnosed with high-risk prostate cancer tend to have high numbers of androgen receptor (AR) in the prostate cancer tissue. Histone deacetylase inhibitors have been proposed as one class of chemicals that might be used effectively to target and down-regulate the androgen receptor with the aim of slowing the rate of prostate cancer progression. Histone deactylase inhibitors have additional effects on genes in cancer cells.

Article Title: Dietary Sulforaphane, a Histone Deacetylase Inhibitor for Cancer Prevention
Authors: Emily Ho, John D. Clarke and Roderick H. Dashwood
J. Nutr. (October 7, 2009).

Previously by this group:
Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in ... mice (2006) FREE .pdf full text


Histone Deacetylases Are Required for Androgen Receptor Function in Hormone-Sensitive and Castrate-Resistant Prostate Cancer
Derek S. Welsbie, Jin Xu, Yu Chen, Laetitia Borsu, Howard I. Scher, Neal Rosen and Charles L. Sawyers
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California and Human Oncology and Pathogenesis Program, Howard Hughes Medical Institute, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York
Cancer Research 69, 958, February 1, 2009.

Transcriptional activity of the androgen receptor (AR) is crucial for growth and survival of prostate cancer even upon development of resistance to androgen ablation and antiandrogen therapies. Therefore, novel therapies that can suppress AR transcriptional activity when conventional hormone therapies fail are needed. Here, we show that histone deacetylase (HDAC) inhibitors, including SAHA (vorinostat) and LBH589 (Panobinostat), which are currently being tested in clinic, could be such a therapy. HDAC inhibitors block the AR-mediated transcriptional activation of many genes, including the TMPRSS2 gene involved in fusion with ETS family members in a majority of prostate cancers. Genetic knockdown of either HDAC1 or HDAC3 can also suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment. Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells, we show that independent of AR protein levels, HDAC inhibitors block AR activity through inhibiting the assembly of coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in castration-resistant prostate cancer models and, therefore, merit clinical investigation in this setting. The HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition."

A Phase 1 clinical trial of vorinostat plus Taxotere ("Phase I Study of Vorinostat in Combination With Docetaxel in Patients With Advanced and Relapsed Solid Malignancies") was terminated in 2008 due to toxicity. This trial was run at University of Michigan Cancer Center. Related US trials are listed here:

IN ADDITION 2 trials of LBH589 (Panobinostat) versus prostate cancer have been terminated for unstated reasons, while 1 other is active and 3 more are recruiting.

Histone Deacetylase Inhibitors Sensitize Prostate Cancer Cells to Agents that Produce DNA Double-Strand Breaks by Targeting Ku70 Acetylation
Chang-Shi Chen and team.
The Ohio State University, Columbus, Ohio; National Taiwan University; The National Health Research Institutes, Taipei, Taiwan; Case Western Reserve University, Cleveland, Ohio
Cancer Research 67, 5318, June 1, 2007
"Overall, the ability of HDAC inhibitors to regulate cellular ability to repair DNA damage by targeting Ku70 acetylation underlies the viability of their combination with DNA-damaging agents as a therapeutic strategy for prostate cancer."

Histone deacetylase inhibitors differentially mediate apoptosis in prostate cancer cells.
Frønsdal K, Saatcioglu F.
Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
Prostate. 2005 Feb 15;62(3):299-306.
".... these results suggest that the response of prostate cancer cells to HDAC inhibitors is not uniform, but cell line and inhibitor specific. Given that prostate cancer is generally a multiclonal disease representing different cell lineages, it is important to develop HDAC inhibitors that will be effective against all of these cell types."

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