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Survivin inhibition via EZN-3042 in canine lymphoma and osteosarcoma

Authors

  • J. K. Shoeneman,

    1. Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
    2. Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, USA
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  • E. J. Ehrhart III,

    1. Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
    2. Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, USA
    3. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
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  • J. B. Charles,

    1. Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
    2. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
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  • D. H. Thamm

    Corresponding author
    1. Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
    2. Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, USA
    • Correspondence address:

      Dr D. H. Thamm

      Flint Animal Cancer Center

      College of Veterinary Medicine and Biomedical Sciences

      Colorado State University

      300 West Drake Road

      Fort Collins

      CO 80523-1620, USA

      e-mail: dthamm@colostate.edu

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Abstract

Canine lymphoma (LSA) and osteosarcoma (OS) have high mortality rates and remain in need of more effective therapeutic approaches. Survivin, an inhibitor of apoptosis (IAP) family member protein that inhibits apoptosis and drives cell proliferation, is commonly elevated in human and canine cancer. Survivin expression is a negative prognostic factor in dogs with LSA and OS, and canine LSA and OS cell lines express high levels of survivin. In this study, we demonstrate that survivin downregulation in canine LSA and OS cells using a clinically applicable locked nucleic acid antisense oligonucleotide (EZN-3042, Enzon Pharmaceuticals, Piscataway Township, NJ, USA) inhibits growth, induces apoptosis and enhances chemosensitivity in vitro, and inhibits survivin transcription and protein production in orthotopic canine OS xenografts. Our findings strongly suggest that survivin-directed therapies might be effective in treatment of canine LSA and OS and support evaluation of EZN-3042 in dogs with cancer.

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