Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available superoxide dismutase

Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, 2-2-2, Iidanishi, Yamagata 990-9585, Japan.
British Journal of Cancer (Impact Factor: 4.84). 04/2006; 94(6):854-62. DOI: 10.1038/sj.bjc.6603016
Source: PubMed


Weakly tumorigenic and nonmetastatic QR-32 cells derived from a fibrosarcoma in C57BL6 mouse are converted to malignant cells once they have grown after being coimplanted with a gelatine sponge which induces inflammation. We administered a newly developed peroral superoxide dismutase (SOD), oxykine, and as control vehicle, gliadin and saline, starting 2 days before the coimplantation and continued daily throughout the experiment. In the oxykine group, tumour incidence was lower (41%) than in the gliadin or saline group (83 and 79%, respectively). The inhibitory effect of oxykine was lost when an individual component of oxykine was administered, that is, SOD alone and gliadin alone. The effect was also abolished when administered by intraperitoneal route. When perfused in situ with nitroblue tetrazolium, an indicator of superoxide formation, the tumour masses from gliadin and saline groups displayed intense formazan deposition, whereas, those from oxykine group had less deposition. Enzymatic activity of SOD was also increased in oxykine group. Arising tumour cells in gliadin and saline groups acquired metastatic phenotype, but those in oxykine group showed reduced metastatic ability. These results suggested that the orally active SOD derivative prevented tumour progression promoted by inflammation, which is thought to be through scavenging inflammatory cell-derived superoxide anion.

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    • "This effect cannot be attributed to limited muscle-cell damage, because GliSODin failed to alter LDH or CPK activity. The results of a few studies suggest that melon extract may have direct antiinflammatory properties (Dugas et al., 2003; Marikovsky, Ziv, Nevo, Harris-Cerruti, & Mahler, 2003; Okada et al. 2006; Vouldoukis et al., 2003). Vouldoukis et al. (2004) observed that melon extract decreased formation of tumor necrosis factor alpha and stimulated production of anti-inflammatory cytokines such as interleukin 10. "
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    ABSTRACT: The aim of this study was to investigate the effect of plant superoxide dismutase extract (GliSODin) supplementation on the balance of oxidants and antioxidants in the serum and erythrocytes of competitive rowers. The double-blinded study included 19 members of the Polish rowing team who were participating in a preparatory camp. Subjects were randomly assigned to the supplemented group (n = 10), who received 2 capsules (500 mg) of GliSODin extract once daily for 6 weeks, or the placebo group (n = 9). At the beginning and end of the study, subjects performed a 2,000-m maximum-effort test on a rowing ergometer. Blood samples were taken from the antecubital vein before each exercise test, 1 min after completing the test, and after a 24-hr restitution period. The following redox parameters were assessed in erythrocytes: superoxide dismutase (SOD) activity, glutathione peroxidase activity, and concentrations of thiobarbituric-acid-reactive substances. In addition, creatine kinase activity and total antioxidant capacity were measured in plasma samples, lactate levels were determined in capillary blood samples, and C-reactive protein and lactate dehydrogenase concentrations were measured in serum. After supplementation, SOD activity was significantly higher (p = .0037) in the supplemented group than the placebo group, and C-reactive protein was significantly (p = .00001) lower in athletes receiving GliSODin than those in the placebo group. In conclusion, supplementation with an extract rich in SOD activity promoted antioxidant status and protected against increased inflammation in the serum of professional rowers but had no effect on oxidative damage induced by exhaustive exercise.
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    • "We previously reported that inflammatory cell infiltration was induced (foreign body-induced inflammation) by implantation of a piece of gelatin sponge subcutaneously into mice. We also demonstrated that the effect of a putatively inhibitory compound against inflammatory cell infiltration could be evaluated by directly counting the infiltrated inflammatory cells after digesting the sponge with collagenase[19]. Similarly, we found that both auraptene and turmerones effectively inhibited infiltration oftory cells into the inserted gelatin sponge (Table 1). "
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    ABSTRACT: Reducing cancer incidence and mortality by use of cancer-chemopreventive agents is an important goal. We have established an in vitro bioassay that is able to screen large numbers of candidate chemicals that are positive for prevention of inflammation-related carcinogenesis. To accomplish this we have added candidate chemicals or vehicles and freshly isolated, fluorescent dye-labeled inflammatory cells that were overlaid on TNF-alpha-stimulated mouse endothelial cells in a 96-well plate. Inhibition of inflammatory cell attachment to the endothelial cells by the chemicals was quantified by the intensity of fluorescence from the adherent inflammatory cells after removing unattached cells. Using this assay, we selected two chemicals, auraptene and turmerones, for further study. As an in vivo test, diets containing these test chemicals were administered to mice with a piece of foreign body, gelatin sponge, that had been implanted to cause inflammation, and we found that the number of inflammatory cells that infiltrated into the subcutaneously implanted gelatin sponge was reduced compared to that found in the mice fed with a control diet. Moreover, diets containing either of the two chemicals prevented inflammation-based carcinogenesis in a mouse model. We found that the compounds reduced not only the number of infiltrating cells but also the expression of inducible nitric oxide synthase (iNOS) or formation of 8-hydroxy-2'-deoxyguanine (8-OHdG) in the infiltrated cells. Moreover, both compounds but not controls sustained the reducing activity in the inflammatory lesion, and this finding was confirmed by using non-invasive in vivo electron spin resonance. The newly established in vitro screening assay will be useful for finding biologically effective chemopreventive agents against inflammation-related carcinogenesis.
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    • "Moreover, cytokines can modulate ROS generation in cells, and immune cells themselves generate ROS (Burdon, 1995). Experimental research has indeed shown that the combination of inflammatory conditions and high ROS levels promotes melanoma progression and metastasis (Okada et al., 2006) and melanoma cell adhesion, extravasation and liver metastasis (Mendoza et al., 2001). In summary, oxidative stress and immune homeostasis are both influenced by gender and are closely intertwined. "
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    ABSTRACT: Epidemiological research consistently shows a female advantage in melanoma survival. So far, no definite candidate for the explanation of this phenomenon has emerged. We propose that gender differences in oxidative stress caused by radical oxygen species (ROS) underlie these survival differences. It is known that males express lower amounts of anti-oxidant enzymes, resulting in more oxidative stress than females. The primary melanoma environment is characterized by high ROS levels, from exogenous sources as well as ROS production within melanoma cells themselves. ROS are known to be able to promote metastasis through a wide variety of mechanisms. We hypothesize that the higher levels of ROS in men enhance selection of ROS-resistance in melanoma cells. Subsequently, ROS can stimulate the metastatic potential of melanoma cells. In addition, due to the lower anti-oxidant defenses in men, ROS produced by melanoma cells cause more damage to healthy tissues surrounding the tumor, further stimulating metastasis. Therefore, ROS may explain the observed differences between males and females in melanoma survival.
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