The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo

Buckley, Megan C.; Yoon, Joanne; Yee, Herman; Chiriboga, Luis; Liebes, Leonard; Ara, Gulshan; Qian, Xiaozhong; Bajorin, Dean F.; Sun, Tung‐Tien; Wu, Xue-Ru; Osman, Iman

doi:10.1186/1479-5876-5-49

Cited by 72 publications

(49 citation statements)

References 38 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dose-dependent upregulation of p21 in tumour cells in the present study are in line with a decreased tumour growth rate after 4-PB treatment (18). Likewise, overexpression of p21 was detected after treatment of bladder and prostate cancer with belinostat, another HDACi (35,36). The present study shows an initial dose-dependent increase within the first 24 h followed by a delayed decrease of p21 upregulation after 24 h. One possible explanation is a sustained protein degradation in the extracellular space in the surroundings of accumulating apoptotic and necrotic cells.…”

Section: Discussionsupporting

confidence: 88%

Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages

Welsch

Welsch²,

Dovzhanskiy³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. Histone deacetylase inhibitors have been found to have potent anticancer activities, partly induced by tumour cell apoptosis. The clearance of apoptotic tumour cells is an important mechanism of antitumour immune surveillance. The aim of this study was to assess the impact of 4-phenylbutyrate (4-PB) and its immunological effects on the macrophage clearance of apoptotic pancreatic ductal adenocarcinoma (PDAC) cells. To this end, a co-culture system of human macrophages from donors and PDAC patients, and PDAC cell lines (T3M4, PANC-1 and AsPC-1) was established to study the effect of 4-PB. Apoptosis and phagocytic activity were analysed using flow cytometry, and phagocytosis was confirmed by confocal microscopy. Further, p21 expression was quantified by immunoblot analysis. 4-PB treatment (0-10 mM) resulted in a dose-dependent induction of tumour cell apoptosis in two of the cell lines (T3M4 and PANC-1), but it also induced human macrophage apoptosis. The apoptotic effect of gemcitabine on PDAC cells was further enhanced by 4-PB. Moreover, 4-PB led to a dose-dependent overexpression of the cell cycle regulator p21 in tumour cells. In co-culture, apoptotic PDAC cells were phagocytosed by donor macrophages and phagocytosis was increased through tumour cell exposure to 4-PB and/or gemcitabine, whereas phagocytosis of PANC-1 cells was reduced using macrophages of PDAC patients treated with 4-PB. The 4-PB treatment induced human macrophage expression of the pro-angiogenic IL-8 and simultaneously inhibited inflammatory cytokine release through modulation of IL-10 and TNFα after phagocytosis of apoptotic PDAC cells. In conclusion, the 4-PB treatment activated tumour cell death in PDAC cells, resulting in tumour cell phagocytosis by macrophages. The latter were characterized by an anti-inflammatory and pro-angiogenic cytokine response demonstrating adverse, tumour-promoting effects of macrophages on tumour cells. Thus, the potential of 4-PB as an anticancer agent against PDAC cannot be reliably assessed without taking into account the complex tumour microenvironment. IntroductionCurrently, pancreatic ductal adenocarcinoma (PDAC) still has an extremely dismal prognosis. The best outcome is achieved through complete tumour resection and adjuvant chemotherapy with 5-fluorouracil (5-FU)-or gemcitabine-based regimens, with a median survival of about 23 months (1-3). Moreover, only 15-20% of patients who present with PDAC are potential candidates for curative resection. Gemcitabine is also the mainstay of palliative chemotherapy. Palliative treatment of locally advanced or metastatic PDAC results in a median survival of 6-7 months (4), reflecting the poor chemotherapeutic response of PDAC and the need for improved chemotherapeutic combinations.Two important processes control the epigenetic modification of the DNA and histones: DNA-methylation and post-translational histone modification (5). An essential mechanism is the reversible acetylation and deacetylation of lysine residues of histones. These reactions are balanc...

show abstract

Section: Discussionsupporting

confidence: 88%

Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages

Welsch

Welsch²,

Dovzhanskiy³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…71,72 In vitro studies have demonstrated that DNA methylation and histone acetylation cooperate in regulating the expression of several genes in prostate-derived cell lines. For example, both histone deacetylase inhibitors (FK228, TSA, PXD101) and a DNA hypomethylating agent (5-azacytidine) exhibited various growth inhibitory effects by inducting apoptosis or p21 induction in vitro 73,74 and in vivo. 74 …”

Section: Dna Hypomethylation In Bcmentioning

confidence: 99%

Epigenetics in bladder cancer

Enokida

Nakagawa

2008

Int J Clin Oncol

View full text Add to dashboard Cite

Bladder cancer (BC) is the second most common malignancy of the genitourinary tract and the second leading cause of cancer death in patients with urinary tract malignancies. DNA methylation and histone modifications are important epigenetic mechanisms of gene regulation and play essential roles both independently and cooperatively in tumor initiation and progression. Aberrant epigenetic events such as DNA hypermethylation and altered histone acetylation have both been observed in bladder cancer, in which they affect a large number of genes. Although the list of aberrantly epigenetically regulated genes continues to grow, combination analysis including several candidate genes has given promising results of potential tumor biomarkers for the early diagnosis and risk assessment of bladder cancer. Thus, large-scale screening of aberrant epigenetic events such as DNA hypermethylation is needed to identify bladder cancer-specific epigenetic fingerprints. The reversibility of epigenetic aberrations has made them attractive targets for cancer treatment with modulators that demethylate DNA and inhibit histone deacetylases, leading to the reactivation of silenced genes. In this review, we examine the current literature on epigenetic changes in bladder cancer and discuss the clinical potential of cancer epigenetics for the diagnosis and treatment of this disease.

show abstract

“…High expression levels of class I HDACs correlated with tumour dedifferentiation and higher proliferative fractions (measured by Ki-67) in urothelial carcinoma, which is in line with in vitro studies showing that high HDAC activity leads to tumour dedifferentiation and enhanced tumour cell proliferation [28][29][30]. Despite the growth inhibitory effects of HDAC-i demonstrated in various cell lines including bladder cancer cells, a broad expression analysis of this attractive target has not been conducted yet [12][13][14][15][16]31,32].…”

Section: Discussionmentioning

confidence: 72%

“…In contrast to these findings, a more recent study of Xu and colleagues reported no difference of expression in the expression levels of HDAC-2 between normal urothelial and bladder cancer tissue as assessed by immunohistochemistry [13]. Few studies have found an effect for HDAC-inhibitors (HDAC-i) in urothelial cancer cell lines [12,[14][15][16][17], however, a broad expression analysis of HDACs in urothelial carcinomas has not been conducted so far. In addition, there is no study available on the prognostic relevance of class I HDACs in bladder cancer.…”

Section: Introductionmentioning

confidence: 93%

920 Expression of Histone Deacetylases 1,2 and 3 in Urothelial Bladder Cancer

Poyet¹,

Jentsch²,

Hermanns³

et al. 2013

Journal of Urology

View full text Add to dashboard Cite

Background: Histone deacetylases (HDACs) are known to be associated with an overexpression in different types of cancer such as colon and prostate cancer. In this study we aimed to evaluate the protein expression of class I HDACs in urothelial carcinoma of the bladder. Methods: A tissue microarray containing 348 tissuesamples from 174 patients with a primary urothelial carcinoma of the bladder was immunohistochemically stained for HDAC 1, 2 and 3. Intensity of staining was evaluated and the association with clinico-pathological features and prognosis was assessed. Results: High HDAC expression levels were found in 40 to 60% of all investigated urothelial carcinomas (HDAC-1: 40%, HDAC-2: 42%, HDAC-3: 59%). HDAC-1 and HDAC-2 were significantly associated with higher tumour grades. Although all three markers could not predict progression in univariate analyses, high HDAC-1 expression was associated with a trend toward poorer prognosis. Patients with high-grade tumours and high expression levels of HDAC-1 were more likely to progress compared to all other patients (p < 0.05). Conclusions: High-grade noninvasive papillary bladder tumours are associated with high expression levels of HDAC-1 and HDAC-2. High grade tumours in combination with high expression of HDAC-1 showed a worse prognosis than the other tumours. The high expression levels of HDACs observed particularly in high grade urothelial bladder cancer clearly warrant subsequent studies on the potential use of HDAC inhibitors as a novel therapeutic approach.

show abstract

The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo

Cited by 72 publications

References 38 publications

Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages

Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages

Epigenetics in bladder cancer

920 Expression of Histone Deacetylases 1,2 and 3 in Urothelial Bladder Cancer

Contact Info

Product

Resources

About