The flavonoid nobiletin (5,6,7,8,3′ ′ ′ ′,4′ ′ ′ ′-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK-1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK-1. The enzymatic activity of MMP-9 expressed in culture medium obtained from a co-culture of TMK-1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration-dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P = = = =0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3/body, P = = = =0.0001). These results suggest that nobiletin may be a candidate anti-metastatic drug for prevention of peritoneal dissemination of gastric cancer. Key words: Flavonoid -Nobiletin -Gastric cancer -Peritoneal dissemination -Matrix metalloproteinaseIn spite of the general decline in gastric cancer rates, this cancer remains one of the most important causes of death among Japanese people. In particular, peritoneal dissemination at the final stage of gastric cancer remains untreatable. Although several trials have attempted to control peritoneal dissemination of gastric cancer by chemotherapy and hyperthermia, no significant prolongation of survival was found. Peritoneal dissemination involves several steps, including tumor cell attachment, invasion and growth in the peritoneum. We investigated the role of matrix metalloproteinases (MMPs) in the invasion and metastasis of gastric cancer, and found a close relationship between MMPs expression and malignant potential of gastric cancer.1, 2) We postulated that an appropriate inhibitor of MMP could prevent peritoneal dissemination by controlling the initial steps, and demonstrated a preventive effect of the MMP inhibitor R-94138 in a peritoneal dissemination model using the human gastric cancer cell line TMK-1 in nude mice.3)The intake of citrus fruits is considered beneficial for health, and in a recent literature review of citrus flavonoids, a broad spectrum of biological activities including anti-carcinogenic and antitumor activities was discussed. It is commonly accepted that cancer formation can be prevented by the ingestion of certain foods, 4) and flavonoids in citrus fruits and juices are among the most prominent cancer-preventing agents. Epidemiological studies have indicated that flavonoid ingestion is associated with a reduced risk of certain forms of cancer. 5) Nobiletin (5,6,7,8,3′, is a polymethoxyflavonoid extracted from Citrus depressa Hayata (Rutaceae), a popular citrus fruit in Okinawa, Japan. Nobiletin is kn...

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Marimastat is a broad-spectrum matrix metalloproteinase (MMP) inhibitor that inhibits almost all major MMPs, key enzymes in gastric cancer invasion and metastasis. We investigated the ability of marimastat to inhibit tumor angiogenesis in the severe combined immuno-deficient (SCID) mouse/human gastric cancer model of peritoneal dissemination. A human stomach adenocarcinoma cell line, TMK-1, was injected intraperitoneally into SCID mice. On the 7th day after tumor inoculation, the administration of marimastat (27 mg/kg/day) was initiated and the treatment was continued for 2 weeks using subcutaneously-inoculating mini-osmotic pumps. On the 21st day, the mice were killed and the disseminated nodules were evaluated. Total weights, numbers, and the microvascular density of the disseminating nodules were significantly lower in mice treated with marimastat compared to the control group. Film in situ zymography demonstrated that net gelatinolytic activity in the tissues was weaker in treated-group nodules than in control-group nodules. Thus, our results suggested that marimastat inhibited peritoneal dissemination of human gastric cancer cells through inhibition of tumor angiogenesis, possibly involving the down-regulation of gelatinases, in SCID mice injected with human gastric cancer cells.