UNIPROT:P04179 - FACTA Search

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Query: UNIPROT:P04179 (MnSOD)
2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sequenced the complete 16.5-kb mitochondrial genome (mtDNA) in 15 pancreatic cancer cell lines and xenografts. Homoplasmic mtDNA somatic mutations and novel variants were identified in nearly all samples. Southern blot analysis and direct sequencing of mutation sites showed that the intracellular mass of mtDNA was greatly (6-8-fold) increased in pancreatic cancer cells in relation to corresponding normal cells; this property accounted for and greatly facilitated the identification of these mutations among the dense desmoplastic host reaction characteristic of primary pancreatic cancers. Structural characteristics and mathematical modeling of the evolution of mtDNA mutations suggested that many of the mutations identified might represent a random evolution of homoplasmic variants, rather than necessarily being a product of selective pressures. Complete sequencing of the nuclear MnSOD gene, which protects cells from the mitogenic and toxic effects of oxygen radicals, did not reveal any mutations. Nevertheless, the nearly ubiquitous prevalence and high copy number of mtDNA mutations suggest that they be considered of promising clinical utility in diagnostic applications.
Cancer Res 2001 Feb 15
PMID:Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations. 1124 24

Intraesophageal administration of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) prior to single fraction radiation has been shown to protect mice from lethal esophagitis. In our study, C3H/HeNsd mice received fractionated radiation in two protocols: (i) 18 Gy daily for four days with MnSOD-PL administration 24 hr prior to the first and third fraction, or (ii) 12 Gy daily for six days with MnSOD-PL 24 hr prior to the first, third, and fifth fraction. Control radiated mice received either no liposomes only or LacZ (bacterial beta-galactosidase gene)-plasmid/liposome (LacZ-PL) by the same schedules. We measured thiol depletion and lipid peroxidation (LP) in whole esophagus and tested the effectiveness of a new plasmid, hemagglutinin (HA) epitope-tagged MnSOD (HA-MnSOD). In fractionation protocols, mice receiving MnSOD-PL, but not LacZ-PL (200 microl of plasmid/liposomes containing 200 microg of plasmid DNA), showed a significant reduction in morbidity, decreased weight loss, and improved survival. Four and seven days after 37 Gy single fraction radiation, the esophagus demonstrated a significant increase in peroxidized lipids and reduction in overall antioxidant levels, reduced thiols, and decreased glutathione (GSH). These reductions were modulated by MnSOD-PL administration. The HA-MnSOD plasmid product was detected in the basal layers of the esophageal epithelium 24 hr after administration and provided significant radiation protection compared to glutathione peroxidase-plasmid/liposome (GPX-PL), or liposomes containing MnSOD protein, vitamin E, co-enzyme Q10, or 21-aminosteroid. Thus, MnSOD-PL administration significantly improved tolerance to fractionated radiation and modulated radiation effects on levels of GSH and lipid peroxidation (LP). These studies provide further support for translation of MnSOD-PL treatment into human esophageal radiation protection.
Int J Cancer 2001 Aug 20
PMID:Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated radiation. 1147 96

Cancer cells are in general low in the enzymatic activities of both manganese-containing (MnSOD) and copper- and zinc-containing superoxide dismutase. We have hypothesized that part of the tumor cell phenotype is due to this loss of enzymatic activity. To test this hypothesis, we have overexpressed MnSOD via plasmid and adenovirus transfection in various cancer cell types and have shown tumor suppression. This tumor suppression is via a noncytotoxic mechanism and probably occurs due to cell-cycle perturbations. We have also shown that MnSOD overexpression causes the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to have increased cytotoxicity. Our hypothesis for the mechanism of action of this combination is that overexpression of MnSOD leads to increased peroxide levels and that BCNU inhibits peroxide removal. We currently are investigating the use of adenovirus MnSOD plus BCNU in the treatment of cancer. Results thus far are consistent with the idea that we can use the alterations in antioxidant enzymes observed in cancer cells to therapeutic advantage.
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PMID:Anticancer therapy by overexpression of superoxide dismutase. 1149 57

ROIs and their scavengers are associated with apoptosis induction by anticancer drugs and gamma-rays, but the details have not been clarified. We examined the effect of transfection of Mn-SOD antisense on apoptosis by 5-FU, PLM, CDDP and gamma-rays using nu/nu mice. After inoculation of Mn-SOD antisense-transfected SCC cells into the subcutis of each mouse's back, they slowly multiplied to form tumors sized 1,460 +/- 70 mm(3) at day 60, while control vector-transfected SCC cells rapidly multiplied, with a mean tumor size of 2,330 +/- 220 mm(3). Inversely, mice in the Mn-SOD antisense group survived longer (mean survival duration 94.4 +/- 12.7 days) compared to those in the empty vector group (67.3 +/- 6.8 days). After treatment with 5-FU (5 microg/day), PLM (50 microg/day), CDDP (10 microg/day) and gamma-rays (2 Gy/day), mean survival times were largely prolonged, to 126.3 +/- 22.7, 123.0 +/- 22.1, 136.3 +/- 24.0 and 143.0 +/- 20.8 days, respectively, while mean survival times in the empty vector group were 91.7 +/- 14.8, 85.7 +/- 13.3, 97.5 +/- 16.0 and 100.7 +/- 17.1 days, respectively. Immunohistologically, tumors in the Mn-SOD antisense group revealed additional nick end-labeled cells compared to those in the empty vector group. In comparison, strong expression of Bax, Bak and p21(waf1/cip1) and suppressed expression of Bcl-2, Bcl-X(L) and COX-2 were observed in the Mn-SOD antisense group and the expression pattern of these proteins was the inverse in the empty vector group. The increased expression of these proapoptotic proteins appeared to be p53-independent because p53 protein expression was not increased in the antisense group. These immunohistologic results were supported by Western blotting of each protein. In conclusion, Mn-SOD antisense transfection is advantageous for apoptosis induction of SCC cells by anticancer drugs and gamma-rays through induction of proapoptotic Bcl-2 family proteins and suppression of antiapoptotic protein expression.
Int J Cancer 2001 Nov
PMID:Mn-SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and gamma-rays regulating expression of the BCL-2 family proteins, COX-2 and p21. 1174 42

Prooxidant effect of chemotherapeutic agents is of significant interest in connection with activation of oxidative stress in cancer cells. Role of development of adaptive antioxidant response to the rise of resistance to cytotoxical effect of doxorubicin (DOX) has been studied in human erythroleukemia K562 cells. Growth of resistance to DOX caused enhancement of antioxidant enzymes (Cu, Zn-SOD, Mn-SOD, catalase) elevation of Mn-SOD activity being predominant. Additional increasing of antioxidant level was elevation of GSH maintenance and level of GST-related enzymes (glutathione peroxidase, glutathione S-transferase, glutathione reductase) in resistance K562/DOX cells. The enhancement of antioxidant system prevented activation of lipid peroxidation. Furthermore, the antioxidant growth caused decrease of level of proteintyrosine kinases, thioredoxin, thioredoxin reductase in contrary to elevation of glutaredoxin activity. Increasing of Bcl-2 and suppression of p53 levels was found to be caused by the change of redox state of K562DOX cells. The data support the suggestion that adaptive antioxidant response to prooxidant effect of DOX promotes the development of cellular drug resistance.
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PMID:[Role of the antioxidant system and redox-dependent regulation of transcription factors bcl-2 and p53 in forming resistance of human K562 erythroleukemia cells to doxorubicin]. 1178 3

NF-kappaB is known to exert a cytoprotective action against TNF-alpha-induced apoptosis. To study the role of NF-kappaB in various TNF-alpha-treated epithelial cell lines, we generated stable transfectants overexpressing a mutated unresponsive form of the IkappaBalpha inhibitor (MT cells). As NF-kappaB prevented TNF-alpha-induced apoptosis in various epithelial cancer cell lines, we searched for NF-kappaB target gene products responsible for this difference of sensitivity. We observed an increased Bcl-X(L) expression level in OVCAR-3 cells compared with OVCAR-3 cells expressing a mutated IkappaBalpha inhibitor (MT cells). Induction of the antioxidant enzyme MnSOD was detected only in TNF-alpha-treated OVCAR, MCF7A/Z and HCT116 cells but not in MT cells. Moreover, reactive oxygen species were involved in TNF-alpha-induced apoptosis, as various antioxidants partially protected these cells from apoptosis. At last, transfection of the MnSOD cDNA in MT cells, which do not express this protein after TNF-alpha stimulation, partially restored resistance to TNF-alpha-induced cell death, as observed by clonogenic assays. However, transfection of the Bcl-X(L) cDNA did not induce any protective effect. Therefore, MnSOD expression is induced by NF-kappaB in epithelial cancer cells in response to TNF-alpha, and is at least partially responsible for their resistance to TNF-alpha-induced apoptosis, presumably through the clearance of death-inducing ROS.
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PMID:NF-kappaB-dependent MnSOD expression protects adenocarcinoma cells from TNF-alpha-induced apoptosis. 1203 30

Kunming mice inoculated with hepatoma cell (H22) suspension subcutaneously at their right axilla were administered orally with antioxidants such as vitamine E, beta-carotene, glutamine, kappa-selenocarrageenan and polysaccharide-peptide of coriolus (PSP) solution. It was found that the inoculated hepatoma growth was suppressed to various extents. The two kinds of polysaccharide antioxidants improved non-specific immunity, enhanced the nitrogen monoxide (NO) content in plasma and strengthened the inhibition of hepatoma. Above antioxidants added in the culture of 7721 human hepatoma cells inhibited the cell proliferation and inducedits apoptosis. Meanwhile, the activity of glutathione peroxidase (GSH-Px) in the plasma of mice increased and the content of malondialdehyde (MDA) decreased. H(2)O(2) in low concentration improved the cancer cell proliferation and inhanced the expression of Mn-SOD c-fos and c-jun, but led to cells apoptosis or necrosis in high concentration. The mechanism of antioxidants inhibiting tumor growth and improving cancer cells apoptosis might be that, on the one hand, the antioxidants blocked the free radicals signal transduction on cancer cells proliferation, and on the other hand, they improved the release of NO through enhancing the non-specific immunity, so inhibiting the cancer cells proliferation directly.
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PMID:Inhibition of Proliferation and Expression of N-ras in Hepatoma Cells by Antioxidation Treatment. 1204 Apr 24

In adrenal glands, oxidative free radicals are synthesized in the course of hormonal production, and enzyme superoxide dismutase (SOD) is considered to scavenge these harmful superoxide radicals and, subsequently, to protect the cells. We studied immunohistochemical localization of Mn (manganese)-SOD and Cu,Zn (copper-zinc)-SOD in human adrenal and its disorders from fetus to adult obtained from autopsy or surgery in order to examine the possible biological significance of these two enzymes. In fetal adrenal (n = 4), Cu,Zn-SOD and Mn-SOD were detected only in the fetal cortex. In adrenal glands from children (n = 21) to adults (n = 15), Mn-SOD immunoreactivity was exclusively detected in adrenal medulla, whereas Cu,Zn-SOD immunoreactivity was present only in adrenocortical parenchymal cells, weakly in the zona glomerulosa, and markedly in the zona reticularis. There were no differences in relative immunointensity and/or patterns of immunolocalization of these two SODs among different age groups. Both Cu,Zn-SOD and Mn-SOD immunoreactivity were detected in compact tumor cells of adrenocortical adenoma (n = 16). Marked immunoreactivity of both Cu,Zn-SOD and Mn-SOD was detected in adrenocortical carcinoma (n = 11) and pheochromocytoma (n = 5). These results indicate that Cu,Zn-SOD and Mu-SOD may play different roles as a scavenger or antioxidants in normal human adrenal glands, i.e., Cu,Zn-SOD as a scavenger of toxic superoxide radicals generated during steroidogenesis and Mn-SOD during catecholamine production. Cu,Zn-SOD and Mn-SOD immunoreactivities detected in adrenal neoplasms are also considered to represent altered expression of these enzymes associated with neoplastic transformation, as reported in other human malignancies.
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PMID:Superoxide Dismutase in Human Adrenal and its Disorders: A Correlation with Development and Neoplastic Changes. 1211 69

Photodynamic therapy (PDT), a promising therapeutic modality for the management of solid tumors, is a two-phase treatment consisting of a photosensitizer and visible light. Increasing evidence indicates that tumor cells in regions exposed to sublethal doses of PDT can respond by rescue responses that lead to insufficient cell death. We decided to examine the role of superoxide dismutases (SODs) in the effectiveness of PDT and to investigate whether 2-methoxyestradiol (2-MeOE(2)), an inhibitor of SODs, is capable of potentiating the antitumor effects of this treatment regimen. In the initial experiment we observed that PDT induced the expression of MnSOD but not Cu,Zn-SOD in cancer cells. Pretreatment of cancer cells with a cell-permeable SOD mimetic, Mn(II)-tetrakis(4-benzoic acid)porphyrin chloride, and transient transfection with the MnSOD gene resulted in a decreased effectiveness of PDT. Inhibition of SOD activity in tumor cells by preincubation with 2-MeOE(2) produced synergistic antitumor effects when combined with PDT in 3 murine and 5 human tumor cell lines. The combination treatment was also effective in vivo producing retardation of the tumor growth and prolongation of the survival of tumor-bearing mice. We conclude that inhibition of MnSOD activity by 2-MeOE(2) is an effective treatment modality capable of potentiating the antitumor effectiveness of PDT.
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PMID:Antitumor effects of photodynamic therapy are potentiated by 2-methoxyestradiol. A superoxide dismutase inhibitor. 1240 96

BACKGROUND: d-alpha-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-alpha-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-alpha-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice were killed at either 2 or 6 weeks after the start of dietary intervention. During necropsy, tumor and host tissues were excised for histology and for biochemical analyses. RESULTS: Tumor growth was significantly reduced by 6 weeks of sE supplementation. Thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were suppressed in tumor and in host tissues in sE supplemented mice. In the sE treated mice, the fatty acid composition of microsomal and mitochondrial membranes of tumor and host tissues had proportionately less linoleic acid (n-6 C 18-2), similar levels of arachidonic acid (n-6 C 20-4), but more docosahexanoic acid (n-3 C 22-6). The sE supplementation had no significant effect on blood counts or on intestinal histology but gave some evidence of cardiac toxicity as judged by myocyte vacuoles and by an indicator of oxidative stress (increased ratio of Mn SOD mRNA over GPX1 mRNA). CONCLUSIONS: At least one of the stereoisomers in sE has antitumor activity. Synthetic vitamin E appears to preferentially stabilize membrane fatty acids with more double bonds in the acyl chain. Although sE suppressed tumor growth and lipid peroxidation, it may have side-effects in the heart.
Cancer Cell Int 2003 Mar 12
PMID:High dietary level of synthetic vitamin E on lipid peroxidation, membrane fatty acid composition and cytotoxicity in breast cancer xenograft and in mouse host tissue. 1269 31

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