Targeting of cell survival genes using small interfering RNAs (siRNAs) enhances radiosensitivity of Grade II chondrosarcoma cells

Authors

  • Dae Won Kim,

    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    Search for more papers by this author
  • Sung Wook Seo,

    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    Search for more papers by this author
  • Samuel K. Cho,

    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    Search for more papers by this author
  • Seong Sil Chang,

    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    Search for more papers by this author
  • Ho Won Lee,

    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    Search for more papers by this author
  • Se Eun Lee,

    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    Search for more papers by this author
  • Joel A. Block,

    1. Section of Rheumatology, Rush University Medical Center, 1725 West Harrison Street Suite 1017, Chicago, Illinois 60612
    Search for more papers by this author
  • Tom K. Hei,

    1. Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street 11th floor, New York, New York 10032
    Search for more papers by this author
  • Francis Y. Lee

    Corresponding author
    1. Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032
    • Department of Orthopaedic Surgery, Center for Orthopaedic Research, Columbia University, 630 West 168th Street BB14-1412 New York, New York 10032. Telephone: 212-305-6605; Fax: 212-305-2741
    Search for more papers by this author

Abstract

The main treatment for chondrosarcoma is surgical resection with a wide margin. However, there are certain chondrosarcomas, such as those found in the pelvis and the spine, which cannot be resected adequately with surgery alone. Unfortunately, most chondrosarcomas are resistant to radiation and chemotherapy. Radiation and chemotherapy are thought to kill chondrosarcoma cells by inducing apoptosis, or programmed cell death. In this article, we hypothesize that antiapoptotic gene silencing enhances radiosensitivity in chondrosarcoma cells by facilitating apoptotic pathways. We knocked down antiapoptotic genes in chondrosarcoma cells using small interfering RNAs (siRNAs). Two well-established Grade II human chondrosarcoma cell lines were pretreated with siRNAs that specifically target mRNAs for Bcl-2, Bcl-xL, or XIAP. The cells were then treated with radiation. Cell death was assessed by flow cytometry. Cell survival and proliferation were measured by clonogenic survival assays. Chondrosarcoma cells exhibited radioresistance and increased the expression of Bcl-2, Bcl-xL, and XIAP in response to radiation. When one of the Bcl-2, Bcl-xL, or XIAP genes was silenced with the corresponding siRNA, radiosensitivity increased up to 9.2-fold (p < 0.05). When two out of the three antiapoptotic mRNAs were knocked down simultaneously, there was an 11.3-fold increase in cell death after radiation (p < 0.05). Our findings support a novel therapeutic concept that gene silencing may be used as a molecular adjuvant therapy for radioresistant sarcomas. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25: 820–828, 2007

Ancillary