Antitumor efficacy of hypothemycin, a new Ras-signaling inhibitor

Jpn J Cancer Res. 1999 Oct;90(10):1139-45. doi: 10.1111/j.1349-7006.1999.tb00688.x.


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.

MeSH terms

  • 3T3 Cells
  • Adenocarcinoma / drug therapy
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms / drug therapy*
  • Endothelial Growth Factors / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, Reporter
  • Genes, ras*
  • Humans
  • Lymphokines / genetics
  • Matrix Metalloproteinases / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Signal Transduction / drug effects*
  • Transcription, Genetic / drug effects
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Zearalenone / analogs & derivatives
  • ras Proteins / physiology*


  • Antineoplastic Agents
  • Endothelial Growth Factors
  • Lymphokines
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • hypothemycin
  • Zearalenone
  • Matrix Metalloproteinases
  • ras Proteins