title: Mechanism of increased coxsackie and adenovirus receptor gene expression and adenovirus uptake by phytoestrogen and histone deacetylase inhibitor in human bladder cancer cells and the potential clinical application.
abstract: Coxsackie and adenovirus receptor (CAR) is known as a principal receptor for adenovirus commonly used as a gene delivery vector. Down-regulation of CAR is often detected in several cancer types. Epigenetic modifiers such as histone deacetylase inhibitor FK228 (depsipeptide) have been shown to increase CAR expression as well as the uptake of adenovirus in bladder cancer in vivo and in vitro, indicating that altered transcriptional regulation of CAR is the key mechanism responsible for the decreased CAR levels in this cancer. In this study, we screened agents that could induce CAR expression in bladder cancer cells. Fifty-eight drugs with various chemical properties were tested. Ipriflavone and plant isoflavones were found to exhibit the ability to induce CAR gene expression in combination with FK228. Genistein, the natural isoflavone found in soybean, when combined with FK228, exerts a synergistic effect on CAR gene and protein expression in bladder cancer cells. Chromatin immunoprecipitation results showed an increased histone acetylation in the CAR promoter gene, which is due to the suppression of histone deacetylase activity by both agents. Also, our data indicated that combination treatment is a potent chemotherapeutic regimen for bladder cancer cells and the subsequent administration of recombinant adenovirus could further eliminate the remaining cells. Taken together, our results provide a strong rationale for combining chemotherapeutic and gene therapeutic agents to enhance the therapeutic efficacy in bladder cancer.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9110, USA.
authors.forename: Rey-Chen
authors.initials: RC
authors.lastname: Pong
authors.forename: Ryan
authors.initials: R
authors.lastname: Roark
authors.forename: Jiun-Yih
authors.initials: JY
authors.lastname: Ou
authors.forename: Jianhai
authors.initials: J
authors.lastname: Fan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stanfield
authors.forename: Eugene
authors.initials: E
authors.lastname: Frenkel
authors.forename: Arthur
authors.initials: A
authors.lastname: Sagalowsky
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity; D002295:Carcinoma, Transitional Cell; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004770:Enterovirus / Q000472:pathogenicity; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D048789:Phytoestrogens / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D011991:Receptors, Virus / Q000187:drug effects* / Q000235:genetics*; D001749:Urinary Bladder Neoplasms
chemical_list: C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D048789:Phytoestrogens; D012333:RNA, Messenger; D011991:Receptors, Virus