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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/16289
Title: 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
University of Kentucky
University of Kentucky College of Medicine
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Oct-2005
Citation: International Journal of Oncology. Vol.27, No.4 (2005), 1047-1052
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-CX, 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-CX, confirming a NF-κBmediated 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.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=33644816509&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/16289
ISSN: 17912423
10196439
Appears in Collections:Scopus 2001-2005

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