title: Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models.
abstract: Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy.
authors.affiliation: Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556 Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Negishi
authors.forename: Masashi
authors.initials: M
authors.lastname: Idogawa
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mita
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D000107:Acetylation; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004268:DNA-Binding Proteins / Q000378:metabolism; D047630:Depsipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C495901:TP53 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C087123:romidepsin; D006655:Histone Deacetylases