title: Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells.
abstract: Epigenetic modifiers such as histone deacetylases (HDACs) have come into focus as novel drug targets for cancer therapy due to their functional role in tumor progression. Since common pan-HDAC inhibitors have adverse side effects and minor anti-cancer activity against solid tumors, enzyme-specific inhibitors were developed. HDAC6 is especially well-suited for specific inhibition due to its unique domain structure and mode of action and has been suggested to provide an exceptionally suitable target for cancer therapy. However, expression and function of HDACs have been insufficiently studied in urothelial cancers (UC), a disease urgently requiring new therapeutic approaches. The present study sought to evaluate HDAC6 as a target for treatment of urothelial cancers with enzyme-specific inhibitors. We observed moderate HDAC6 overexpression in urothelial cancer tissues and a broad range of expression in urothelial cancer cell lines. In the cell lines Tubacin was the most potent inhibitor, compared with Tubastatin and ST-80, but still active only at high micromolar concentrations. HDAC6 expression levels correlated poorly with sensitivity to enzyme inhibition. Combined treatments with heat shock, HSP90 inhibition by 17-AAG, proteasome inhibition by bortezomib, or DNA-damaging agents did not result in significant synergistic effects. Experiments with siRNA-mediated knockdown further underlined that urothelial cancer cells do not critically depend on HDAC6 expression for survival.
authors.affiliation: Department of Urology; Heinrich-Heine-University; Medical Faculty; Duesseldorf, Germany.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rosik
authors.affiliation: Department of Urology; Heinrich-Heine-University; Medical Faculty; Duesseldorf, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Niegisch
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology; Heinrich-Heine-University; Medical Faculty; Duesseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Institute of Pharmaceutical Sciences; University of Freiburg; Freiburg, Germany; German Cancer Consortium (DKTK); Heidelberg, Germany; German Cancer Research Center (DKFZ); Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: Department of Urology; Heinrich-Heine-University; Medical Faculty; Duesseldorf, Germany.
authors.forename: Wolfgang Arthur
authors.initials: WA
authors.lastname: Schulz
authors.affiliation: Department of Urology; Heinrich-Heine-University; Medical Faculty; Duesseldorf, Germany.
authors.forename: Michèle Janine
authors.initials: MJ
authors.lastname: Hoffmann
mesh_terms: D000107:Acetylation; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008875:Middle Aged; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D019459:Urothelium / Q000473:pathology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D016227:Benzoquinones; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D047029:Lactams, Macrocyclic; D011719:Pyrazines; C474316:tubacin; C553587:tubastatin A; C112765:tanespimycin; D000069286:Bortezomib; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: 17-AAG; HDAC; HDAC inhibitor; ST-80; Tubacin; Tubastatin; bortezomib; urothelial cancer