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

Grimes, Kristopher R.; Daosukho, Chotiros; Zhao, Yunfeng; Meigooni, Ali S.; Clair, William St

doi:10.3892/ijo.27.4.1047

Cited by 9 publications

(12 citation statements)

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“…MnSOD is a primary antioxidant responsible for scavenging superoxide in the mitochondria. It has been shown in previous studies that radiation-induced MnSOD protein leads to enhanced radiation resistance (18,(31)(32)(33). It has also been shown that PGE 2 , a major product of arachodonic metabolism, can activate NF-κB via the transactivation domain of Rel A (15).…”

Section: Discussionmentioning

confidence: 99%

“…Mice were weighed and tumors were measured weekly. Tumors were measured and irradiated according to previous studies (18). Slopes were calculated using the general trend lines of each treatment group.…”

Section: Methodsmentioning

confidence: 99%

“…Protein concentrations were analyzed using a standard Bradford protein assay (Bio-Rad Laboratories, Richmond, CA, USA), 30 μg of protein was separated on a 12% SDS-polyacrylamide electrophoresis mini gel at 120 V for 1 h. Proteins were then transferred to a nitrocellulose membrane (Schleicher & Schuell, Keene, NH, USA) at 100 V for 1.5 h. Membranes were probed with anti-MnSOD (Upstate) at a dilution of 1:3000, survivin (Novus) at a dilution of 1:2000, and then stripped for 45 min at 55˚C and normalized to anti-ß-actin (Sigma) with a dilution of 1:2000. Measurement and detection of proteins were determined as previously demonstrated (18,19).…”

Section: Methodsmentioning

confidence: 99%

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Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo

Grimes

Warren²,

Fang³

et al. 2006

Oncol Rep

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Abstract. Lung cancer is the leading cause of cancer-related deaths in the United States. Despite improvements in radiation, surgery and chemotherapy the 5 year survival statistics of non-small cell lung cancer (NSCLC) have improved little over the past two decades. It has been proposed that NF-κB is a participant in the cytoprotection against several redox-mediated therapeutic agents including ionizing radiation. Cyclooxygenase-2 (COX-2) inhibition has become an attractive target for enhancing the efficacy of radiation and chemotherapy. Numerous mechanistic pathways have been proposed as the means through which COX-2 inhibition enhances the efficacy of radiation. We hypothesize that the COX-2 inhibitor, nimesulide, will improve the efficacy of radiation therapy (RT), at least in part, via the suppression of NF-κB mediated cytoprotective pathways. In this study we used the COX-2 inhibitor nimesulide to improve the efficacy of RT when measured by tumor regrowth assays in vivo and clonegenic survival in vitro. For the in vivo assay, A549 tumor cells representing NSCLC were subcutaneously injected into the right flanks of female athymic nude mice (n=10/group). Mice were given nimesulide via drinking water at a concentration of 5 μg/g body weight (b.w.) and the water was replenished daily. Tumors were treated with 30 Gy fractionated radiation and measured biweekly. For our in vitro study, clonogenic survival assays were evaluated to determine the effect of nimesulide, radiation, and the combination. The NF-κB mediated mechanism of nimesulide was measured by Western blot analysis of NF-κB target genes, MnSOD and survivin. In vivo, mice that received combined treatments of 5 μg/g b.w. nimesulide and 30 Gy radiation (3 Gy/fraction, 10 daily fractions) had significant reduction in tumor size in comparison to the 30 Gy radiation control group (p<0.05). In vitro, nimesulide alone produced a significant decrease in clonogenic survival at doses from 0-300 μM. Nimesulide demonstrated an additive effect in combination with radiation. Nimesulide alone reduced MnSOD and survivin protein levels in a dose-dependent manner. 6 Gy radiation caused an initial elevation of MnSOD protein levels which was inhibited by prior treatment of nimesulide suggesting an inhibition of radiation induced NF-κB target genes. These results support the hypothesis that COX-2 inhibitors such as nimesulide can increase the efficacy of radiation therapy. In vitro, our results suggest that the radiosensitization of A549 tumor cells by nimesulide is mediated by the suppression of NF-κB-mediated, radiation-induced cytoprotective genes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo

Grimes

Warren²,

Fang³

et al. 2006

Oncol Rep

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“…In order to explain the mechanism of radiosensitizing effect, proteasome inhibitors including MG132 have been studied at high concentration (µM) inducing apoptosis (8,10,16), which might not be applicable to clinical treatment for human cancer.…”

Section: C-myc Down-regulation Is Involved In Proteasome Inhibitor-mementioning

confidence: 99%

“…The combination of bortezomib with IR induced nuclear factor-κB (NF-κB) inhibition, apoptosis, and cytokines, which was associated with tumor control in head and neck cancer model (12), colorectal cancer model (13) as well as in androgen independent human prostate cancer cells (8). MG132 has been reported to sensitize PC-3 prostate cancer cells to IR by NF-κB inhibition (14,15) and improve the radiotherapeutic effect in NSCLC (16).…”

Section: Introductionmentioning

confidence: 99%

c-Myc down-regulation is involved in proteasome inhibitor-mediated enhancement of radiotherapeutic efficacy in non-small cell lung cancer

Jung

Kim²,

Chung³

et al. 2011

Int J Oncol

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Abstract. In this study, the effect of MG132 (carbobenzoxylleucinyl-leucinyl-leucinal-H) at a low dose on radiotherapeutic efficacy and its accurate mechanism of radiosensitization were investigated in human non-small cell lung cancer. The effect of MG132 on ionizing radiation (IR)-induced cytotoxicity, cell proliferation and survival of A549 cells was evaluated. The protein expression modulated by MG132 and IR were inspected by Western blot analysis. To determine in vivo radiotherapeutic efficacy, tumor growth delay was analyzed in a A549 tumorbearing xenograft mouse model after single or repeated treatment of MG132 and/or IR. Induction of apoptosis and change of c-Myc expression in the tumor tissue was explored by histological analysis. MG132 at a non-toxic dose enhanced the radiationinduced cytotoxicity of A549 cells, accompanying a significant decrease of c-Myc expression. Suppression of c-Myc expression by small interfering RNA (siRNA) displayed enhancement of radiosensitivity similarly to MG132 treatment. Tumor growth in the xenograft mice was markedly delayed by systemic administration of MG132 combined with IR. In vivo down-regulation of c-Myc and increased induction of apoptosis were simultaneously observed in the tumor tissues followed by combinational treatment of MG132 and IR. The results reveal a novel mechanism for proteasome inhibitor-mediated radiosensitization in which c-Myc down-regulation is involved.

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Anorexia–Cachexia syndrome in cancer: implications of the ubiquitin–proteasome pathway

Camps

Iranzo

Bremnes

et al. 2006

Support Care Cancer

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The ubiquitin-proteasome system is the most important pathway of protein degradation. As a regulatory system governing protein half-life, it is involved in the regulation of the cell cycle, signal transmission, immune system response, apoptosis, and oncogenesis. Knowledge of the molecular pathways involved in the induction of cancer-associated cachexia will favor a more rational approach to its treatment as well as possible quality of life and survival benefit for the patient.

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

Cited by 9 publications

References 0 publications

Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo

Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo

c-Myc down-regulation is involved in proteasome inhibitor-mediated enhancement of radiotherapeutic efficacy in non-small cell lung cancer

Anorexia–Cachexia syndrome in cancer: implications of the ubiquitin–proteasome pathway

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