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

Buckley MT, Yoon J, Yee H, Chiriboga L, Liebes L, Ara G, Qian X, Bajorin DF, Sun TT, Wu XR, Osman I - J Transl Med (2007)

Bottom Line: Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed.Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM).Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Urology, New York University School of Medicine, New York, USA. mike.buckley@med.nyu.edu

ABSTRACT

Background: Treatment options for patients with recurrent superficial bladder cancer are limited, necessitating aggressive exploration of new treatment strategies that effectively prevent recurrence and progression to invasive disease. We assessed the effects of belinostat (previously PXD101), a novel histone deacetylase inhibitor, on a panel of human bladder cancer cell lines representing superficial and invasive disease, and on a transgenic mouse model of superficial bladder cancer.

Methods: Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed. Ha-ras transgenic mice with established superficial bladder cancer were randomized to receive either belinostat or vehicle alone, and assessed for bladder weight, hematuria, gene expression profiling, and immunohistochemistry (IHC).

Results: Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM). The 5637 cell line, which was derived from a superficial papillary tumor, was the most sensitive to treatment. Belinostat (100 mg/kg, intraperitoneal, 5 days each week for 3 weeks) treated mice had less bladder weight (p < 0.05), and no hematuria compared with 6/10 control mice that developed at least one episode. IHC of bladder tumors showed less cell proliferation and a higher expression of p21WAF1 in the belinostat-treated mice. Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes.

Conclusion: Our data demonstrate that belinostat inhibits bladder cancer and supports the clinical evaluation of belinostat for the treatment of patients with superficial bladder cancer.

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Inhibition of bladder cancer cell proliferation by belinostat at 1, 2 and 5 μM for 48 h in the human urinary bladder cancer cell lines 5637, T24, J82 and RT4. Percent inhibition from control was determined using the WST-1 tetrazolium salt cleavage assay. Bars are representative of at least 3 independent experiments and are the mean of at least 8 wells per condition. Error bars indicate SEM.
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Figure 1: Inhibition of bladder cancer cell proliferation by belinostat at 1, 2 and 5 μM for 48 h in the human urinary bladder cancer cell lines 5637, T24, J82 and RT4. Percent inhibition from control was determined using the WST-1 tetrazolium salt cleavage assay. Bars are representative of at least 3 independent experiments and are the mean of at least 8 wells per condition. Error bars indicate SEM.

Mentions: The in vitro treatment of all four urothelial carcinoma cell lines at 1–5 μM belinostat for 48 h caused a dose-dependent inhibition of proliferation, with the most potent inhibitory effect occurring on 5637 cells (IC50 of 1.0 μM), and the least effect occurring on RT4 cells (IC50 of 10.0 μM). T24 and J82 cell lines had an IC50 of 3.5 and 6.0 μM, respectively. Treatment with 5 μM belinostat for 48 h caused a 71% (± 0.2, SEM) decrease in cell growth and proliferation for 5637 cells, 51% (± 1.0) for T24, 41% (± 2.0) for J82, and 23% (± 7.9) for RT4 cells (Figure 1). All cell lines, except the RT4 line, showed a significant growth inhibition (GI) when compared to control at all concentrations of belinostat (1, 2 and 5 μM) (p < 0.001). RT4 cells only showed a significant GI at 5 μM belinostat when compared to control (p = 0.01).


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

Buckley MT, Yoon J, Yee H, Chiriboga L, Liebes L, Ara G, Qian X, Bajorin DF, Sun TT, Wu XR, Osman I - J Transl Med (2007)

Inhibition of bladder cancer cell proliferation by belinostat at 1, 2 and 5 μM for 48 h in the human urinary bladder cancer cell lines 5637, T24, J82 and RT4. Percent inhibition from control was determined using the WST-1 tetrazolium salt cleavage assay. Bars are representative of at least 3 independent experiments and are the mean of at least 8 wells per condition. Error bars indicate SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2100044&req=5

Figure 1: Inhibition of bladder cancer cell proliferation by belinostat at 1, 2 and 5 μM for 48 h in the human urinary bladder cancer cell lines 5637, T24, J82 and RT4. Percent inhibition from control was determined using the WST-1 tetrazolium salt cleavage assay. Bars are representative of at least 3 independent experiments and are the mean of at least 8 wells per condition. Error bars indicate SEM.
Mentions: The in vitro treatment of all four urothelial carcinoma cell lines at 1–5 μM belinostat for 48 h caused a dose-dependent inhibition of proliferation, with the most potent inhibitory effect occurring on 5637 cells (IC50 of 1.0 μM), and the least effect occurring on RT4 cells (IC50 of 10.0 μM). T24 and J82 cell lines had an IC50 of 3.5 and 6.0 μM, respectively. Treatment with 5 μM belinostat for 48 h caused a 71% (± 0.2, SEM) decrease in cell growth and proliferation for 5637 cells, 51% (± 1.0) for T24, 41% (± 2.0) for J82, and 23% (± 7.9) for RT4 cells (Figure 1). All cell lines, except the RT4 line, showed a significant growth inhibition (GI) when compared to control at all concentrations of belinostat (1, 2 and 5 μM) (p < 0.001). RT4 cells only showed a significant GI at 5 μM belinostat when compared to control (p = 0.01).

Bottom Line: Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed.Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM).Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Urology, New York University School of Medicine, New York, USA. mike.buckley@med.nyu.edu

ABSTRACT

Background: Treatment options for patients with recurrent superficial bladder cancer are limited, necessitating aggressive exploration of new treatment strategies that effectively prevent recurrence and progression to invasive disease. We assessed the effects of belinostat (previously PXD101), a novel histone deacetylase inhibitor, on a panel of human bladder cancer cell lines representing superficial and invasive disease, and on a transgenic mouse model of superficial bladder cancer.

Methods: Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed. Ha-ras transgenic mice with established superficial bladder cancer were randomized to receive either belinostat or vehicle alone, and assessed for bladder weight, hematuria, gene expression profiling, and immunohistochemistry (IHC).

Results: Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM). The 5637 cell line, which was derived from a superficial papillary tumor, was the most sensitive to treatment. Belinostat (100 mg/kg, intraperitoneal, 5 days each week for 3 weeks) treated mice had less bladder weight (p < 0.05), and no hematuria compared with 6/10 control mice that developed at least one episode. IHC of bladder tumors showed less cell proliferation and a higher expression of p21WAF1 in the belinostat-treated mice. Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes.

Conclusion: Our data demonstrate that belinostat inhibits bladder cancer and supports the clinical evaluation of belinostat for the treatment of patients with superficial bladder cancer.

Show MeSH
Related in: MedlinePlus