Hypoxia-Response Plasmid Vector Producing bcl-2 shRNA Enhances the Apoptotic Cell Death of Mouse Rectum Carcinoma

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  • Fujioka Takashi
    Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan
  • Matsunaga Naoya
    Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan
  • Okazaki Hiroyuki
    Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan
  • Koyanagi Satoru
    Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan
  • Ohdo Shigehiro
    Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Japan

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Abstract

Hypoxia-induced gene expression frequently occurs in malignant solid tumors because they often have hypoxic areas in which circulation is compromised due to structurally disorganized blood vessels. Hypoxia-response elements (HREs) are responsible for activating gene transcription in response to hypoxia. In this study, we constructed a hypoxia-response plasmid vector producing short hairpin RNA (shRNA) against B-cell leukemia/lymphoma-2 (bcl-2), an anti-apoptotic factor. The hypoxia-response promoter was made by inserting tandem repeats of HREs upstream of cytomegalovirus (CMV) promoter (HRE-CMV). HRE-CMV shbcl-2 vector consisted of bcl-2 shRNA under the control of HRE-CMV promoter. In hypoxic mouse rectum carcinoma cells (colon-26), the production of bcl-2 shRNA driven by HRE-CMV promoter was approximately 2-fold greater than that driven by CMV promoter. A single intratumoral (i.t.) injection of 40 μg HRE-CMV shbcl-2 to colon-26 tumor–bearing mice caused apoptotic cell death, and repetitive treatment with HRE-CMV shbcl-2 (40 μg/mouse, i.t.) also significantly suppressed the growth of colon-26 tumor cells implanted in mice. Apoptotic and anti-tumor effects were not observed in tumor-bearing mice treated with CMV shbcl-2. These results reveal the ability of HRE-CMV shbcl-2 vector to suppress the expression of bcl-2 in hypoxic tumor cells and suggest the usefulness of our constructed hypoxia-response plasmid vector to treat malignant tumors.<BR>[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10054FP]

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