Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

Abstract

Histone deacetylase inhibitors (HDACs) are known to exhibit antiproliferative effects on various carcinoma cells. In this study, the in vivo efficiency of two HDACs, sodium butyrate and tributyrin, on prostate cancer growth inhibition were investigated. To gain an insight into the possible underlying pathways, cell culture experiments were performed focusing on the expression of p21, Rb and cmyc. For in vivo testing, prostate cancer cell lines (PC3 and TSU-Pr1) were seeded on the chorioallantois membrane (CAM) and implanted in a xenograft model using nude mice. Standard Western blot analysis was performed for protein expression of p21, Rb and c-myc in HDAC-treated vs untreated prostate cancer cells. Both sodium butyrate and tributyrin had a considerable treatment effect on microtumours on the chicken egg at already very low concentrations of 0.1 mM. Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3. In the mouse model, there was almost no difference between sodium butyrate and tributyrin. In untreated animals the tumours were almost double the size 4 weeks after implantation. Tumours of the treatment groups had a significantly lower percentage of Ki-67-positive-stained nuclei. As demonstrated by Western blot analysis, these effects seem to be independent of p53 status and a pathway via p21 -Rb -c-myc is possibly involved. In this study we have demonstrated a substantial in vivo treatment effect, which can be induced by the application of sodium butyrate or the orally applicable tributyrin in human prostate cancer. The given results may provide the rationale to apply these drugs in well-controlled clinical trials in patients being at high risk of recurrence after specific therapy or in patients with locally or distant advanced prostate cancer.

Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

“…Functionally, a growth inhibition of prostate cancer cells by administration of HDIs has already been shown both in vitro and in animal models (Butler et al, 2000;Kuefer et al, 2004;Thelen et al, 2004;Fronsdal and Saatcioglu, 2005;Gediya et al, 2005;Myzak et al, 2006). Divergent effects of therapeutic concentrations of the HDAC inhibitors SAHA and VPA on tumour cell cycle, with the former inducing a G 2 /M arrest and the latter inducing a G 1 arrest, were reported for other tumour cell lines as well (Takai et al, 2004a, b).…”

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

“…The authors concluded that the low-dose decitabine regime was well-tolerated with a modest clinical activity. Although a number of HDAC inhibitors have shown promising antitumour activity in animal models of prostate cancer (36,43,44), as yet there are no published clinical trials in humans. A number of phase I trials have however reported good clinical efficacy and a favourable side-effect profile for HDAC inhibitors in a range of other solid and haematological malignancies (45).…”

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

“…Importantly, pre-exposure to MS-275-sensitized primary medulloblastoma cells to Doxorubicin-or VP16-induced apoptosis in a dose-dependent manner (Figure 4a). Finally, we evaluated the anti-tumor activity of the combination treatment in vivo using the chorioallantoic membrane model, an established in vivo model of cancer including medulloblastoma (Kuefer et al, 2004;Vogler et al, 2008;Hacker et al, 2009). Intriguingly, the combination of MS-275 and Doxorubicin was significantly more effective to suppress medulloblastoma growth in vivo compared with treatment with either Doxorubicin or MS-275 alone (Figure 4b).…”