title: Histone deacetylase inhibitors upregulate plakoglobin expression in bladder carcinoma cells and display antineoplastic activity in vitro and in vivo.
abstract: Histone deacetylase inhibitors (HDACis) are emerging as a promising new class of anticancer agents displaying growth-inhibitory activity and low toxicity in vivo. In this study, we examined the effect of sodium butyrate (NaB) and trichostatin A (TSA) on the growth of human bladder carcinoma cell lines in culture and TSA on the growth of EJ and UM-UC-3 human bladder xenografts in nude mice. NaB and TSA suppressed the growth of bladder cell lines at millimolar (1.5-4.3 mM) and micromolar (0.03-0.33 microM) concentrations, respectively, inducing concentration-dependent cell death. Bladder carcinoma cells within the experimental panel displayed the phenotype of late-stage bladder lesions expressing N-cadherin in the absence of E-cadherin accompanied by low levels of plakoglobin expression. Exposure of these cells to HDACis resulted in upregulation of plakoglobin with no change in E-cadherin expression. A 2-hr exposure to TSA was the minimal time required to upregulate plakoglobin in cells with downregulation to baseline levels occurring within 24 hr following drug removal. In mice bearing EJ and UM-UC-3 bladder xenografts, TSA (500 microg/kg/day) caused suppression of tumor growth compared with mice receiving vehicle alone. A > 70% reduction in mean final tumor volume was recorded in both bladder xenograft models with no detectable toxicity. The results suggest that TSA inhibits bladder carcinoma cell growth and may be a useful, relatively nontoxic agent for consideration in the treatment of late-stage bladder tumors.
authors.affiliation: Department of Urology, Lahey Clinic Medical Center, Burlington, MA 01805, USA.
authors.forename: David
authors.initials: D
authors.lastname: Canes
authors.forename: George J
authors.initials: GJ
authors.lastname: Chiang
authors.forename: Brian R
authors.initials: BR
authors.lastname: Billmeyer
authors.forename: Christina A
authors.initials: CA
authors.lastname: Austin
authors.forename: Monika
authors.initials: M
authors.lastname: Kosakowski
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Rieger-Christ
authors.forename: John A
authors.initials: JA
authors.lastname: Libertino
authors.forename: Ian C
authors.initials: IC
authors.lastname: Summerhayes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002087:Butyrates / Q000627:therapeutic use*; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051180:Desmoplakins; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051185:gamma Catenin
chemical_list: D000970:Antineoplastic Agents; D002087:Butyrates; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051185:gamma Catenin; C012589:trichostatin A