Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells

Abstract

Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables such as broccoli. The ability of SFN to inhibit histone deacetylase enzymes may be one mechanism by which it acts as a chemoprevention agent. The ability of a chemopreventive agent to specifically cause cytotoxicity in cancer, not normal cells is an important factor in determining its safety and clinical relevance. We characterized the effects of SFN in normal (PrEC), benign hyperplasia (BPH1) and cancerous (LnCap and PC3) prostate epithelial cells. We observed that 15 µM SFN selectively induced cell cycle arrest and apoptosis in BPH1, LnCap and PC3 cells but not PrEC cells. SFN treatment also selectively decreased HDAC activity, and Class I and II HDAC proteins, increased acetylated histone H3 at the promoter for P21, induced p21 expression and increased tubulin acetylation in prostate cancer cells. HDAC6 over-expression was able to reverse SFN-induced cyotoxicity. In PrEC cells, SFN caused only a transient reduction in HDAC activity with no change in any other endpoints tested. The differences in sensitivity to SFN in PrEC and PC3 are likely not due to differences in SFN metabolism or differences in phase 2 enzyme induction. From these data we conclude that SFN exerts differential effects on cell proliferation, HDAC activity and downstream targets in normal and cancer cells.

Effect of Sulforaphane in Men with Biochemical Recurrence after Radical Prostatectomy

“…Epigenetic regulation could be the key factor, as GSTP1 and GSTM1 hypermethylation and HDACs are prominently involved in prostate carcinogenesis and it has been shown that sulforaphane suppresses both of these mechanisms (24,25,37). These questions will be explored in future trials.…”

“…HDACs are a group of enzymes that are involved in epigenetic gene silencing (23,24,25). For some authors, both DNA demethylation and HDAC inhibition are required to induce complete gene expression of epigenetically silenced genes (26) and sulforaphane fulfills both criteria.…”

Challenging Oneself Intermittently to Improve Health

“…In prostate cancer cells sulforaphane can cause glutathione depletion which triggers mitochondrial membrane depolarization, release of cytochrome c and activation of caspases (Singh et al, 2005). The reason that, at a given concentration, sulforaphane can kill cancer cells but not normal cells is poorly understood but may involve inhibition of histone deacetylases in the cancer cells (Clarke et al, 2011) and differential effects on mitogen-activated protein kinases in normal and cancer cells (Zeng et al, 2011). The anti-cancer effects of curcumin may involve mechanisms that overlap with those of sulforaphane.…”

Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity

“…In addition to increasing cellular capacity for detoxifying electrophiles and oxidants, SFN has been shown to induce apoptosis, and to inhibit cell cycle progression and angiogenesis [14][15][16][17][18][19]. Most recently, SFN has also been shown to induce antiproliferative effects via epigenetic mechanisms [20], namely acting as dietary histone deacetylase inhibitor through its metabolite SFN-cysteine 3 [21,22], and to suppress DNA methylation [23].…”