The Citrus Flavonoid, Nobiletin, Inhibits Peritoneal Dissemination of Human Gastric Carcinoma in SCID Mice

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 metallo–proteinase (proMMP)–l, 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.