Abstract. Docetaxel (DTX) is used for the treatment of advanced hormone refractory prostate cancer. Connexin 43 (Cx43) is a tumor suppressor gene, and transfection of the Cx43 gene increases sensitivity to several chemotherapeutic agents. The objective of this study was to evaluate the effectiveness of combination therapy of Cx43-expressing plasmid DNA (pCMV-Cx43) and DTX both in vitro and in vivo using a non-viral vector in human prostate cancer PC-3 cells. Transfection of pCMV-Cx43 into the cells neither inhibited tumor growth nor increased gap junctional intercellular communication; however, combination therapy of pCMVCx43 and DTX significantly inhibited cell growth. Forced expression of Cx43 in the cells induced apoptotic cells by down-regulation of Bcl-2 expression and significantly more up-regulation of caspase-3 activity than either treatment alone. The combination of repeated intratumoral injection of pCMV-Cx43 (10 μg/tumor) with non-viral vector and a single intravenous injection of DTX (15 mg/kg) was compared with a repeated injection of Cx43 alone and a single injection of DTX alone on PC-3 tumor xenografts. Significant antitumoral effects were observed in mice receiving combined treatment, compared with DTX alone. The data presented here provide a rational strategy for treating patients with advanced hormone refractory prostate cancer.
We report that STZ-induced diabetic mice exhibited decreased Adipo levels and hyperglycemia which may be alleviated by hydrodynamic injection of the Adipo gene. This type of gene delivery system to the liver offers a different approach in developing novel treatments for type 1 and 2 diabetes.
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.
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