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

• Published in: Journal of translational medicine 2007-10, Vol.5 (1), p.49-49, Article 49
• Main Authors: Buckley, Michael T, Yoon, Joanne, Yee, Herman, Chiriboga, Luis, Liebes, Leonard, Ara, Gulshan, Qian, Xiaozhong, Bajorin, Dean F, Sun, Tung-Tien, Wu, Xue-Ru, Osman, Iman
• Format: Article
• Language: English
• Subjects: Animals; Antimitotic agents; Antineoplastic agents; Bladder cancer; Cancer cells; Care and treatment; Cell Communication - drug effects; Cell Communication - genetics; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Control; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Drug Screening Assays, Antitumor; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Hematuria - complications; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids - adverse effects; Hydroxamic Acids - pharmacology; Immunohistochemistry; Male; Mice; Mice, Transgenic; Organ Size - drug effects; Sulfonamides; Urinary Bladder Neoplasms - complications; Urinary Bladder Neoplasms - enzymology; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/1479-5876-5-49

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