migrastatin and Breast-Neoplasms

A significantly simpler analog of the natural product migrastatin, termed migrastatin ether (ME), has been prepared and evaluated. Both in vivo and in vitro studies indicate that ME exhibits a concentration-dependent inhibitory effect on migration of breast cancer cells.

Topics: Animals; Antineoplastic Agents; Biological Products; Breast Neoplasms; Cell Movement; Drug Screening Assays, Antitumor; Ethers; Female; Humans; Macrolides; Mice; Molecular Conformation; Neoplasm Metastasis; Piperidones; Stereoisomerism

Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

Topics: Actins; Animals; Antineoplastic Agents; Binding Sites; Breast Neoplasms; Carrier Proteins; Cell Line, Tumor; Cell Movement; Crystallography, X-Ray; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Macrolides; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Microfilament Proteins; Models, Molecular; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidones; Protein Conformation

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Movement; Female; Humans; Lactones; Macrolides; Models, Chemical; Piperidones; Quinic Acid; Tumor Cells, Cultured

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.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Humans; Lactones; Lung Neoplasms; Macrolides; Mice; Neoplasm Metastasis; Piperidones; rac GTP-Binding Proteins