Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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-kappaB 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-kappaB 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 microg/g body weight (b.w.) and the water was replenished daily. Tumors were treated with 30 Gy fractionated radiation and measured bi-weekly. For our in vitro study, clonogenic survival assays were evaluated to determine the effect of nimesulide, radiation, and the combination. The NF-kappaB mediated mechanism of nimesulide was measured by Western blot analysis of NF-kappaB target genes, MnSOD and survivin. In vivo, mice that received combined treatments of 5 microg/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 microM. 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-kappaB 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-kappaB-mediated, radiation-induced cytoprotective genes.
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PMID:Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo. 1696 92

Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.
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PMID:Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. 2250 79