Abstract
We have established an inflammation-related carcinogenesis model in mouse, in which regressive QR-32 cells subcutaneously co-implanted with a foreign body—gelatin sponge—convert themselves into lethal tumors due to massive infiltration of inflammatory cells into the sponge. Animals were fed with a diet containing 5% or 10% fermented brown rice and rice bran with Aspergillus oryzae (FBRA). In 5% and 10% FBRA diet groups, tumor incidences were lower (35% and 20%, respectively) than in the non-treated group (70%). We found that FBRA reduced the number of inflammatory cells infiltrating into the sponge. FBRA administration did not cause myelosuppression, which indicated that the anti-inflammatory effects of FBRA took place at the inflammatory lesion. FBRA did not have antitumor effects on the implanted QRsP-11 tumor cells, which is a tumorigenic cell line established from a tumor arisen after co-implantation of QR-32 cells with sponge. FBRA did not reduce formation of 8-hydroxy-2′-deoxyguanine adducts, a marker of oxidative DNA damage in the inflammatory lesion; however, it reduced expression of inflammation-related genes such as TNF-α, Mac-1, CCL3 and CXCL2. These results suggest that FBRA will be an effective chemopreventive agent against inflammation-related carcinogenesis that acts by inhibiting inflammatory cell infiltration into inflammatory lesions.
Highlights
Since a possible link between inflammation and carcinogenesis was first indicated by Rudolf Virchow in the 19th century, results from animal and epidemiological studies have supported his hypothesis [1]
Taking the analysis results of our inflammation-related carcinogenesis model into consideration, we assumed four possible mechanisms/hypotheses for the suppression of carcinogenesis by FBRA ingestion: (i) By reduction of infiltration of inflammatory cells (17); (ii) By suppressing the production of reactive oxygen species (ROS)/nitric oxide derived from inflammatory cells [19,20], even if infiltration of inflammatory cells is not suppressed; (iii) By elimination of inflammatory-cells-derived ROS through antioxidative enzymes induced at inflamed lesions [34]; and (iv) By specific cytotoxicity to the malignantly converted QR-32 cells by inflammation
Considering the close link between inflammation and carcinogenesis, side-effect-free agents are needed to prevent/treat inflammation, since steroidal drugs and non-steroid anti-inflammatory drugs (NSAIDs) often accompany unfavorable adverse effects when used for controlling persistent inflammatory diseases
Summary
Since a possible link between inflammation and carcinogenesis was first indicated by Rudolf Virchow in the 19th century, results from animal and epidemiological studies have supported his hypothesis [1]. The International Agency for Research on Cancer evaluates that typical NSAIDs such as aspirin and sulindac are chemopreventive agents [6], and that aspirin is effective against colon carcinogenesis [7]. In this regard, NSAIDs are promising chemopreventive drugs; use of NSAIDs causes unexpected lethal side effects, such as cardiovascular disease, ulcerating disease, hypertension and acute renal failure in some cases [8]; to avoid them, safe compounds with antiphlogistic effects are needed. We report that FBRA reduced the frequency of inflammation-related carcinogenesis through suppression of inflammatory cell infiltration into the inflamed sites by inhibiting the expression of inflammation-related genes
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