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

Abstract

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.

Antioxidant enzymes and cancer

“…Inflammation in the lung contributing high level of Mn-SOD was supposed to lead to increase H 2 O 2 intracellularly and create an intracellular environment favorable to DNA damage and the promotion of cancer [14] . However, the orally active SOD derivative prevented tumor progression promoted by inflammation, which is thought to be through the scavenging inflammatory cell-derived superoxide anion [15] . Er et al [16] reported the differential expression of SOD in patients with breast cancer in Taiwan.…”

Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis

“…Mice receiving protandim diet showed reduced oxidative and inflammatory responses as evidenced by decreased protein carbonyl levels as well as suppression of the PKC-JNK-Jun and NF-κB signaling (82). Administration of oxykine, an orally active SOD, to mice co-implanted with a weakly tumorigenic and non-metastatic fibrosarcoma-derived QR-32 cells and inflammation-inducing gelatin sponge, resulted in the reduced tumor incidence, increased SOD activity, and decreased deposition of formazan upon in situ perfusion of tumor tissue with nitroblue tetrazolium (an indicator of superoxide formation) (83). Fibrosarcoma-derived (QR-32) cells implanted with an inflammation inducer in this study acquired a reduced metastatic phenotype by scavenging inflammatory cell-derived superoxide anion (83).…”

Beyond foreign‐body‐induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression

“…The prevention was actually achieved by induction of Mn-SOD at the coimplantation site by administering Mn-SOD-inducible biological response modifier 109 or orally available superoxide dismutase in this system. 110 Moreover, it is assumed that RNS are partially involved in the model, because administration of a broad inhibitor for inducible nitric oxide significantly inhibited inflammation-induced tumor progression. 93 By extensively analyzing human tissue materials obtained from typical inflammation-based carcinogenesis, it has been revealed that ROS and RNS are inevitably involved in the development and progression of tumors.…”