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Article

Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation

  • Authors:
    • Wilhelmina C.M. Duivenvoorden
    • Sarah N. Hopmans
    • Daniel Gallino
    • Thomas Farrell
    • Carrie Gerdes
    • Diana Glennie
    • Himu Lukka
    • Jehonathan H. Pinthus
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Division of Urology, McMaster University, Hamilton, ON, Canada, Department of Medical Physics, McMaster University, Hamilton, ON, Canada, Juravinski Cancer Centre, Hamilton, ON, Canada
  • Pages: 1968-1976
    |
    Published online on: August 7, 2015
       https://doi.org/10.3892/or.2015.4184
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Abstract

While normal kidneys are relatively sensitive to ionizing radiation (IR), renal cell carcinoma (RCC) is considered radioresistant. Carbonic anhydrase IX (CA9), an enzyme that maintains intracellular pH by carbon dioxide dissolution, is upregulated in the majority of RCC, but not in normal kidneys. Since regulation of intracellular pH may enhance radiation effects, we hypothesized that inhibition of CA9 may radiosensitize RCC. Clonogenic survival assay of human clear cell RCC 786-O and murine RCC RAG cells in the presence of a pharmacological CA9 inhibitor or with shRNA-mediated knockdown of CA9 was performed to investigate the response to IR in vitro (single dose or fractionated) and in vivo. Extracellular pH changes were measured in vitro. Treatment with AEBS [4-(2-aminoethyl)benzene sulfonamide], a sulfonamide, was used as a pharmacological inhibitor of the enzymatic activity of CA9. Nude mice bearing subcutaneous xenografts of 786-O cells stably expressing CA9 shRNA or scrambled control were irradiated (6 Gy). Tumor growth was followed longitudinally in the 786-O-bearing mice receiving AEBS (50-200 µg/ml drinking water) or control (vehicle only) which were irradiated (6 Gy) and compared with mice receiving either IR or AEBS alone. In vitro inhibition of CA9 activity or expression significantly sensitized RCC cells to the effects of IR (p<0.05), an effect even more significant when hypofractionated IR was applied. In vivo irradiated xenografts from RCC cells transfected with CA9 shRNA were significantly smaller compared to irradiated xenografts from the scrambled shRNA controls (p<0.05). RCC xenografts from mice treated with AEBS in combination with IR grew significantly slower than all controls (p<0.05). Inhibition of CA9 expression or activity resulted in radiation sensitization of RCC in a preclinical mouse model.
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Copy and paste a formatted citation
Spandidos Publications style
Duivenvoorden WC, Hopmans SN, Gallino D, Farrell T, Gerdes C, Glennie D, Lukka H and Pinthus JH: Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation. Oncol Rep 34: 1968-1976, 2015.
APA
Duivenvoorden, W.C., Hopmans, S.N., Gallino, D., Farrell, T., Gerdes, C., Glennie, D. ... Pinthus, J.H. (2015). Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation. Oncology Reports, 34, 1968-1976. https://doi.org/10.3892/or.2015.4184
MLA
Duivenvoorden, W. C., Hopmans, S. N., Gallino, D., Farrell, T., Gerdes, C., Glennie, D., Lukka, H., Pinthus, J. H."Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation". Oncology Reports 34.4 (2015): 1968-1976.
Chicago
Duivenvoorden, W. C., Hopmans, S. N., Gallino, D., Farrell, T., Gerdes, C., Glennie, D., Lukka, H., Pinthus, J. H."Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation". Oncology Reports 34, no. 4 (2015): 1968-1976. https://doi.org/10.3892/or.2015.4184
Copy and paste a formatted citation
x
Spandidos Publications style
Duivenvoorden WC, Hopmans SN, Gallino D, Farrell T, Gerdes C, Glennie D, Lukka H and Pinthus JH: Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation. Oncol Rep 34: 1968-1976, 2015.
APA
Duivenvoorden, W.C., Hopmans, S.N., Gallino, D., Farrell, T., Gerdes, C., Glennie, D. ... Pinthus, J.H. (2015). Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation. Oncology Reports, 34, 1968-1976. https://doi.org/10.3892/or.2015.4184
MLA
Duivenvoorden, W. C., Hopmans, S. N., Gallino, D., Farrell, T., Gerdes, C., Glennie, D., Lukka, H., Pinthus, J. H."Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation". Oncology Reports 34.4 (2015): 1968-1976.
Chicago
Duivenvoorden, W. C., Hopmans, S. N., Gallino, D., Farrell, T., Gerdes, C., Glennie, D., Lukka, H., Pinthus, J. H."Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation". Oncology Reports 34, no. 4 (2015): 1968-1976. https://doi.org/10.3892/or.2015.4184
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