Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: An antioxidant connection

  • Authors:
    • Kristopher Ray Grimes
    • Chotiros Daosukho
    • Yunfeng Zhao
    • Ali Meigooni
    • William St. Clair
  • View Affiliations

  • Published online on: October 1, 2005     https://doi.org/10.3892/ijo.27.4.1047
  • Pages: 1047-1052
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Abstract

Non-small cell lung cancer frequently presents as a locally advanced disease. In this setting, radiation has a prominent role in cancer therapy. However, tumor adaptation to oxidative stress may lessen the efficacy of radiation therapy. Recent studies demonstrate that proteasome inhibitors increase the efficacy of radiation against a range of tumors. Although proteasome inhibition impacts on NF-κB translocation, the precise mechanism through which proteasome inhibitors induce tumor cell death and promote radiation efficacy remains unclear. The purpose of this study is to evaluate the potential of the proteasome inhibitor, MG-132, to improve the efficacy of radiation therapy and to determine whether its effect is linked to the suppression of the antioxidant enzyme, manganese superoxide dismutase (MnSOD). Human NSCLC (A549) cells were utilized both in vivo and in vitro to evaluate proteasome inhibition on radiation response. In vivo, mice that received combined treatments of 2.5 µg/g body weight MG-132 and 30 Gy demonstrated a delay in tumor regrowth in comparison to the 30 Gy control group. In vitro, clonegenic survival assays confirmed a dose-dependent enhancement of radiation sensitivity in combination with MG-132 and a significant interaction between the two. The levels of IκB-α, a NF-κB target gene and also an inhibitor of NF-κB nuclear translocation, decreased in a time-dependent manner following administration of MG-132 confirming the inhibition of the 26S proteasome. The MnSOD protein level was increased consistent with lower levels of IκB-α, confirming a NF-κB-mediated effect. Cells treated with radiation demonstrated an induction of MnSOD; however, the administration of MG-132 suppressed this induction These results support the hypothesis that proteasome inhibitors such as MG-132 can increase the efficacy of radiation therapy, in part, by suppression of cytoprotective NF-κB-mediated MnSOD expression.

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October 2005
Volume 27 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Grimes KR, Daosukho C, Zhao Y, Meigooni A and St. Clair W: Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: An antioxidant connection. Int J Oncol 27: 1047-1052, 2005.
APA
Grimes, K.R., Daosukho, C., Zhao, Y., Meigooni, A., & St. Clair, W. (2005). Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: An antioxidant connection. International Journal of Oncology, 27, 1047-1052. https://doi.org/10.3892/ijo.27.4.1047
MLA
Grimes, K. R., Daosukho, C., Zhao, Y., Meigooni, A., St. Clair, W."Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: An antioxidant connection". International Journal of Oncology 27.4 (2005): 1047-1052.
Chicago
Grimes, K. R., Daosukho, C., Zhao, Y., Meigooni, A., St. Clair, W."Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: An antioxidant connection". International Journal of Oncology 27, no. 4 (2005): 1047-1052. https://doi.org/10.3892/ijo.27.4.1047