Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the apogossypol derivative BI-97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells

Authors

  • Belal Azab,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Rupesh Dash,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Swadesh K. Das,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Sujit K. Bhutia,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    Current affiliation:
    1. Department of Life Science, National Institute of Technology, Rourkela, Orissa, India.
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  • Xue-Ning Shen,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Bridget A. Quinn,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Siddik Sarkar,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Xiang-Yang Wang,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    2. VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    3. VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Michael Hedvat,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    2. Sanford-Burnham Medical Research Institute, La Jolla, California
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  • Igor P. Dmitriev,

    1. Department of Radiation Oncology, School of Medicine, Washington University, St. Louis, Missouri
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  • David T. Curiel,

    1. Department of Radiation Oncology, School of Medicine, Washington University, St. Louis, Missouri
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  • Steven Grant,

    1. VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    2. VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    3. Department of Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Paul Dent,

    1. VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    2. VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    3. Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • John C. Reed,

    1. Sanford-Burnham Medical Research Institute, La Jolla, California
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  • Maurizio Pellecchia,

    1. Sanford-Burnham Medical Research Institute, La Jolla, California
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  • Devanand Sarkar,

    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    2. VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    3. VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
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  • Paul B. Fisher

    Corresponding author
    1. Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    2. VCU Institute of Molecular Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    3. VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
    • Department of Human and Molecular Genetics, School of Medicine, VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
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Abstract

Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an effective wide-spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5-mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3-mda-7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3-mda-7. A combination regimen of suboptimal doses of Ad.5/3-mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5-mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3-mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients. J. Cell. Physiol. 227: 2145–2153, 2012. © 2011 Wiley Periodicals, Inc.

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