title: Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: an antioxidant connection.
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-kappaB 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 microg/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 IkappaB-alpha, a NF-kappaB target gene and also an inhibitor of NF-kappaB 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 IkappaB-alpha, confirming a NF-kappaB-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-kappaB-mediated MnSOD expression.
authors.affiliation: Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Kristopher Ray
authors.initials: KR
authors.lastname: Grimes
authors.forename: Chotiros
authors.initials: C
authors.lastname: Daosukho
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ali
authors.initials: A
authors.lastname: Meigooni
authors.forename: William
authors.initials: W
authors.lastname: St Clair
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D018384:Oxidative Stress; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D021381:Protein Transport; D011836:Radiation Tolerance; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000975:Antioxidants; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D000072000:NF-KappaB Inhibitor alpha; D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde