Shan Dandan, Chen Lin, Njardarson Jon T, Gaul Christoph, Ma Xiaojing, Danishefsky Samuel J, Huang Xin-Yun
Department of Physiology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3772-6. doi: 10.1073/pnas.0500658102. Epub 2005 Feb 22.
Tumor metastasis is the most common cause of death in cancer patients. Here, we show that two, fully synthetic migrastatin analogues, core macroketone and core macrolactam, are potent inhibitors of metastasis in a murine breast tumor model. Administration of these readily accessible compounds nearly completely inhibits lung metastasis of highly metastatic mammary carcinoma cells. Treatment of tumor cells with core macroketone and core macrolactam blocks Rac activation, lamellipodia formation, and cell migration, suggesting that these chemical compounds interfere with the invasion step of the metastatic process. These compounds also inhibit the migration of human metastatic breast cancer cells, prostate cancer cells, and colon cancer cells but not normal mammary-gland epithelial cells, fibroblasts, and leukocytes. These data demonstrate that the macroketone and macrolactam core structures are specific small-molecule inhibitors of tumor metastasis. These compounds or their analogues could potentially be used in cancer-therapy strategies.
肿瘤转移是癌症患者最常见的死亡原因。在此，我们表明两种完全合成的米格拉他汀类似物，核心大环酮和核心大环内酰胺，在小鼠乳腺肿瘤模型中是有效的转移抑制剂。给予这些易于获得的化合物几乎完全抑制高转移性乳腺癌细胞的肺转移。用核心大环酮和核心大环内酰胺处理肿瘤细胞可阻断Rac激活、板状伪足形成和细胞迁移，这表明这些化合物干扰了转移过程的侵袭步骤。这些化合物还抑制人转移性乳腺癌细胞、前列腺癌细胞和结肠癌细胞的迁移，但不抑制正常乳腺上皮细胞、成纤维细胞和白细胞的迁移。这些数据表明，大环酮和大环内酰胺核心结构是肿瘤转移的特异性小分子抑制剂。这些化合物或其类似物有可能用于癌症治疗策略。
