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.
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.
Hattori
Yoshiyuki
Y
Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan. yhattori@hoshi.ac.jp
Fukushima
Masayoshi
M
Maitani
Yoshie
Y
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
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