title: Non-viral delivery of the connexin 43 gene with histone deacetylase inhibitor to human nasopharyngeal tumor cells enhances gene expression and inhibits in vivo tumor growth.
abstract: Dysregulation of connexin expression is believed to have a role in carcinogenesis, because levels of connexin are reduced in various tumors. We examined the role of connexin 43 (Cx43) alone and combined with a histone deactylase (HDAC) inhibitor in tumor growth inhibition. The transfection of Cx43 plasmid DNA (pCMV-Cx43) into human nasopharyngeal cancer KB cells using folate-linked nanoparticles induced inhibition of cell growth. Cx43 induced a tumor suppressive effect via a gap junctional intercellular communication-independent mechanism. The transfection of pCMV- Cx43 along with an HDAC inhibitor, 4-phenylbutyrate (4-PB), enhanced Cx43 expression greatly in vitro, and inhibited significantly the tumor growth of KB cells and xenografts compared with that of pCMV-Cx43 alone. 4-PB induced increased expression of genes of DNA damage checkpoints and of apoptosis via the down-regulation of anti-apoptotic bcl-2 mRNA expression and up-regulation of the activity of the apoptosis-associated enzyme caspase-3/7. Thus, the amplified Cx43 expression by an antitumor agent, an HDAC inhibitor, may have great potential as a growth inhibitor for nasopharyngeal tumors.
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan. yhattori@hoshi.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukushima
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Maitani
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018031:Connexin 43 / Q000008:administration & dosage* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000627:therapeutic use; D009303:Nasopharyngeal Neoplasms / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D010654:Phenylbutyrates / Q000008:administration & dosage*; D010957:Plasmids; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018031:Connexin 43; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C075773:4-phenylbutyric acid; D053148:Caspase 3; D053179:Caspase 7