Antitumor Efficacy of Hypothemycin, A New Ras‐signaling Inhibitor

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‐β (TGF‐β), 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‐? 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.