manumycin and Fibrosarcoma

Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding lectin, has been reported to display remarkable anti-proliferative and apoptosis-inducing activities toward a variety of cancer cells; however, the precise molecular mechanisms by which PCL induces cancer cell death are still elusive. In the current study, we found that PCL could induce apoptosis and autophagy in murine fibrosarcoma L929 cells. Subsequently, we demonstrated that inhibition of Ras could promote L929 cell death, suggesting that Ras-Raf signaling pathway plays the key negative regulator in PCL-induced apoptosis. And, we showed that Ras-Raf signaling pathway was also involved in PCL-induced autophagy as the negative regulator. In addition, we found that class I phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway could play the negative regulator in PCL-induced apoptosis and autophagy. Taken together, these results demonstrate that PCL induces murine fibrosarcoma L929 cell apoptosis and autophagy via blocking Ras-Raf and PI3K-Akt signaling pathways.

Topics: Androstadienes; Animals; Apoptosis; Autophagy; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Fibrosarcoma; Heterocyclic Compounds, 4 or More Rings; Indoles; Mice; Microscopy, Electron, Transmission; Phenols; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Plant Lectins; Polyenes; Polygonatum; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; raf Kinases; ras Proteins; Signal Transduction; Tetrazoles; Time Factors; Wortmannin

A microbial screen using a yeast strain with conditional deficiency in the GPA1 gene was carried out to search for inhibitors of protein farnesyltransferase (PFT). A strain of Streptomyces was found to produce active compounds named UCF1-A, UCF1-B, and UCF1-C. Structural determination of these compounds revealed that UCF1-C is identical to the known antibiotic, manumycin, whereas UCF1-A and UCF1-B are structurally related to manumycin. All three UCF1 compounds suppress the lethality of gpa1 disruption, with UCF1-C exhibiting the strongest activity. UCF1 inhibits yeast as well as rat brain PFT. Fifty percent inhibition of yeast PFT activity is observed with 5 microM UCF1-C. Kinetic analyses of the inhibition suggest that UCF1-C acts as a competitive inhibitor of PFT with respect to farnesyl pyrophosphate, exhibiting a Ki of 1.2 microM, whereas the same compound appears to act as a noncompetitive inhibitor of PFT with respect to the farnesyl acceptor, the Ras protein. UCF1-C shows significant activity to inhibit the growth of Ki-ras-transformed fibrosarcoma, raising the possibility of its use as an antitumor drug.

Topics: Alkyl and Aryl Transferases; Amino Acid Sequence; Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Brain; Cattle; Cell Transformation, Neoplastic; Fibrosarcoma; Genes, Fungal; Genes, Lethal; Genes, ras; Glutathione Transferase; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Molecular Structure; Neoplasm Transplantation; Polyenes; Polyunsaturated Alkamides; Rats; Recombinant Fusion Proteins; Saccharomyces cerevisiae; Streptomyces; Structure-Activity Relationship; Transferases; Transplantation, Heterologous; Tumor Cells, Cultured