hypothemycin and Colonic-Neoplasms

Aigialomycins A-E (2-6), new 14-membered resorcylic macrolides, were isolated together with a known hypothemycin (1) from the mangrove fungus, Aigialus parvus BCC 5311. Structures of these compounds, including absolute configuration, were elucidated by spectroscopic methods, chemical conversions, and X-ray crystallographic analysis. Hypothemycin and aigialomycin D (5) exhibited in vitro antimalarial activity with IC(50) values of 2.2 and 6.6 microg/mL, respectively, while other analogues were inactive. Cytotoxicities of these compounds were also evaluated.

Topics: Animals; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Antiprotozoal Agents; Ascomycota; Botrytis; Breast Neoplasms; Chlorocebus aethiops; Chromatography, High Pressure Liquid; Colonic Neoplasms; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; KB Cells; Kidney; Leukemia; Leukemia P388; Macrolides; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Plasmodium falciparum; Tetrahymena; Thailand; Ustilago; Vero Cells; Zearalenone

We have devised a new drug screening assay to discover anti-cancer drugs which inhibit Ras-mediated cellular signals, by utilizing a Ras-responsive element (RRE)-driven reporter gene system. We found that hypothemycin, an anti-bacterial, reduces RRE-dependent transcription. Treatment of tumor cells with hypothemycin resulted in reduced expression of Ras-inducible genes, including MMP (matrix metalloproteinase)-1, MMP-9, transforming growth factor-beta (TGF-beta), and vascular endothelial growth factor (VEGF), but not that of the constitutively expressed gene, MMP-2. The results of zymography demonstrated that hypothemycin reduced the production of MMP-9 and MMP-3, another Ras-inducible MMP, in the culture medium. Hypothemycin selectively inhibits anchorage-independent growth of Ras-transformed cells in comparison with anchorage-dependent growth. These findings suggest that hypothemycin inhibits Ras-mediated cellular signaling. Daily treatment of tumor-bearing mice with hypothemycin resulted in significant inhibition of tumor growth. Since MMP-1, MMP-3 and MMP-9 play important roles in tumor invasion and TGF-beta and VEGF are involved in tumor angiogenesis, hypothemycin is considered to be an example of a new class of antitumor drugs, whose antitumor efficacy can be at least partly attributed to inhibition of Ras-inducible genes.

Topics: 3T3 Cells; Adenocarcinoma; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Colonic Neoplasms; Endothelial Growth Factors; Female; Gene Expression Regulation, Neoplastic; Genes, ras; Genes, Reporter; Humans; Lymphokines; Matrix Metalloproteinases; Mice; Mice, Inbred BALB C; Mice, Nude; ras Proteins; Signal Transduction; Transcription, Genetic; Transfection; Transforming Growth Factor beta; Transplantation, Heterologous; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Zearalenone