Minagawa A, Otani Y, Kubota T, Wada N, Furukawa T, Kumai K, Kameyama K, Okada Y, Fujii M, Yano M, Sato T, Ito A, Kitajima M
Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Jpn J Cancer Res. 2001 Dec;92(12):1322-8. doi: 10.1111/j.1349-7006.2001.tb02156.x.
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.
黄酮类化合物川陈皮素（5,6,7,8,3',4'-六甲氧基黄酮）存在于日本冲绳一种受欢迎的柑橘类水果——芸香科的温州蜜柑中，据报道，它在体外可抑制兔滑膜成纤维细胞中前基质金属蛋白酶（proMMP）-1、3和9的产生。在本研究中，我们证明了川陈皮素对癌细胞系TMK-1的增殖及其基质金属蛋白酶（MMP）产生的抑制作用。在重症联合免疫缺陷（SCID）小鼠模型中，我们发现川陈皮素可抑制TMK-1腹膜播散结节的形成。川陈皮素以浓度依赖的方式抑制了从TMK-1与小鼠成纤维细胞共培养获得的培养基中表达的MMP-9的酶活性。在SCID小鼠模型中，治疗组播散结节的总重量显著低于载体对照组（0.07 g对0.78 g，P = 0.0059）。播散结节的总数也显著低于载体对照组（7.5对69.3个/只动物，P = 0.0001）。这些结果表明，川陈皮素可能是一种用于预防胃癌腹膜播散的抗转移候选药物。
