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-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.
Tanaka
H
H
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka.
Nishida
K
K
Sugita
K
K
Yoshioka
T
T
D016475:3T3 Cells; D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000188:drug therapy*; D016228:Endothelial Growth Factors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D011905:Genes, ras; D006801:Humans; D008222:Lymphokines / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D015025:Zearalenone / Q000031:analogs & derivatives; D018631:ras Proteins / Q000502:physiology*
D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C120440:hypothemycin; D015025:Zearalenone; D020782:Matrix Metalloproteinases; D018631:ras Proteins