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

Abstract

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...

Nobiletin, a Citrus Flavonoid, Down-Regulates Matrix Metalloproteinase-7 (matrilysin) Expression in HT-29 Human Colorectal Cancer Cells

“…23) But, the effects of NOB on other members of the MMP family remain to be addressed. Herein, we report for the first time that NOB is a distinct suppressant of MMP-7 expression, while abrogation of AP-1 DNA binding activity might, at least in part, be involved in its action mechanisms, supporting the previous notion that NOB is a promising dietary compound for cancer prevention strategies.…”

“…Moreover, thecatenin/TCF complex is known to cooperate with AP-1 for maximum expression. 14) While there are a large number of reports regarding MMP-9 suppressants, including catechins, 15) curcumin, 16) 1,25-dihydroxyvitamin D 3 , 17) peroxisome proliferator-activated receptor (PPAR) activators, 18) inhibitors of cyclooxygenase (COX) and phospholipase A 2 , 19) and nobiletin (NOB), [20][21][22][23] those for MMP-7 are limited (e.g., retinoic acid, 24) butyrate, 25) and PPAR agonist troglitazone 26) ). In the present study, we investigated the expression of MMPs in human colorectal cancer cell lines and found a high level of MMP-7 mRNA in HT-29 cells.…”

A Photon Counting Technique for Quantitatively Evaluating Progression of Peritoneal Tumor Dissemination

“…For monitoring the progression of tumor dissemination, the only possible method was to implant the tumor cells into groups of mice and sacrifice the animals at different points of time for autopsy and observation; quantitative comparison was still not possible by this method (10)(11)(12)(18)(19)(20)(21)(22)(23)(24)(25).…”

“…Evaluation of the efficacy of anticancer agents was also hampered by this limitation (21)(22)(23)(24)(25). Evaluation using these methods may be affected by subjective factors and, therefore, unsatisfactory from the viewpoint of quantitative or objective evaluation.…”

Volatile Organic Components of Fresh Leaves as Indicators of Indigenous and Cultivated Citrus Species in Taiwan

“…Nobiletin extracted from C. depressa could suppress the production of matrix metalloproteinase, decrease the symptoms of osteoarthritis and rheumatoid arthritis, and also function as an anti-inflammatory, anti-allergic and anticancer agent. 9,10) The contribution of the variability of secondary metabolites to plant taxonomy has been reported. Sixty-six citrus species and near-citrus relatives could be cited in accordance with Tanaka's classification system with 24 flavonoids.…”