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Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice.

TitleSynthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice.
Publication TypeJournal Article
Year of Publication2005
AuthorsShan D, Chen L, Njardarson JT, Gaul C, Ma X, Danishefsky SJ, Huang X-Y
JournalProc Natl Acad Sci U S A
Volume102
Issue10
Pagination3772-6
Date Published2005 Mar 08
ISSN0027-8424
KeywordsAnimals, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Female, Humans, Lactones, Lung Neoplasms, Macrolides, Mice, Neoplasm Metastasis, Piperidones, rac GTP-Binding Proteins
Abstract

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.

DOI10.1073/pnas.0500658102
Alternate JournalProc Natl Acad Sci U S A
PubMed ID15728385
PubMed Central IDPMC553334

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