moverastin-a and Neoplasms

Topics: Animals; Antineoplastic Agents; Benzaldehydes; Biological Products; Cyclohexanones; Drug Design; Enzyme Inhibitors; Farnesyltranstransferase; Gene Targeting; Humans; Neoplasms; Peptide Library; Protein Sorting Signals; ras Proteins; rhoB GTP-Binding Protein

Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Aspergillus; Benzaldehydes; Cell Line, Tumor; Cell Membrane; Cell Movement; Cyclohexanones; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Neoplasms; ras Proteins; Signal Transduction; Stereoisomerism