Abstract
Yondelis is a potent DNA-binding anticancer drug isolated from the tunicate Ecteinascidia turbinata currently undergoing phase III clinical trials. We and others have shown selective inhibition to the transcriptional induction of several genes. We tested the hypothesis that Yondelis specifically targets cell-cycle genes. Our analysis on endogenous and transfected reporter systems revealed complex patterns of transcriptional inhibition and, surprisingly, activation. Other inducible systems - the metallothionein and the CYP3A4 promoters - were little affected. We assayed whether interference of DNA binding of the common nuclear factor Y (NF-Y) activator was responsible for the observed inhibition: in vivo chromatin immunoprecipitation analysis in NIH3T3 and HCT116 cells indicates that NF-Y binding is little affected by Yondelis addition. Finally, histone acetylation was modestly affected only on Cdc2 and cyclin B2 but not on other repressed promoters. These data prove that Yondelis is not a general inhibitor of inducible genes, and its selective effects are exerted downstream from transcription factors binding and histone acetyl transferases recruitment.
| Original language | English |
|---|---|
| Pages (from-to) | 1496-1503 |
| Number of pages | 8 |
| Journal | Molecular Pharmacology |
| Volume | 68 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Nov 2005 |
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- Pharmacology
Cite this
Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters. / Minuzzo, Mario; Ceribelli, Michele; Pitarque-Martì, Marià; Borrelli, Serena; Erba, Eugenio; DiSilvio, Alberto; D'Incalci, Maurizio; Mantovani, Roberto.
In: Molecular Pharmacology, Vol. 68, No. 5, 11.2005, p. 1496-1503.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters
AU - Minuzzo, Mario
AU - Ceribelli, Michele
AU - Pitarque-Martì, Marià
AU - Borrelli, Serena
AU - Erba, Eugenio
AU - DiSilvio, Alberto
AU - D'Incalci, Maurizio
AU - Mantovani, Roberto
PY - 2005/11
Y1 - 2005/11
N2 - Yondelis is a potent DNA-binding anticancer drug isolated from the tunicate Ecteinascidia turbinata currently undergoing phase III clinical trials. We and others have shown selective inhibition to the transcriptional induction of several genes. We tested the hypothesis that Yondelis specifically targets cell-cycle genes. Our analysis on endogenous and transfected reporter systems revealed complex patterns of transcriptional inhibition and, surprisingly, activation. Other inducible systems - the metallothionein and the CYP3A4 promoters - were little affected. We assayed whether interference of DNA binding of the common nuclear factor Y (NF-Y) activator was responsible for the observed inhibition: in vivo chromatin immunoprecipitation analysis in NIH3T3 and HCT116 cells indicates that NF-Y binding is little affected by Yondelis addition. Finally, histone acetylation was modestly affected only on Cdc2 and cyclin B2 but not on other repressed promoters. These data prove that Yondelis is not a general inhibitor of inducible genes, and its selective effects are exerted downstream from transcription factors binding and histone acetyl transferases recruitment.
AB - Yondelis is a potent DNA-binding anticancer drug isolated from the tunicate Ecteinascidia turbinata currently undergoing phase III clinical trials. We and others have shown selective inhibition to the transcriptional induction of several genes. We tested the hypothesis that Yondelis specifically targets cell-cycle genes. Our analysis on endogenous and transfected reporter systems revealed complex patterns of transcriptional inhibition and, surprisingly, activation. Other inducible systems - the metallothionein and the CYP3A4 promoters - were little affected. We assayed whether interference of DNA binding of the common nuclear factor Y (NF-Y) activator was responsible for the observed inhibition: in vivo chromatin immunoprecipitation analysis in NIH3T3 and HCT116 cells indicates that NF-Y binding is little affected by Yondelis addition. Finally, histone acetylation was modestly affected only on Cdc2 and cyclin B2 but not on other repressed promoters. These data prove that Yondelis is not a general inhibitor of inducible genes, and its selective effects are exerted downstream from transcription factors binding and histone acetyl transferases recruitment.
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UR - http://www.scopus.com/inward/citedby.url?scp=27544493942&partnerID=8YFLogxK
U2 - 10.1124/mol.105.013615
DO - 10.1124/mol.105.013615
M3 - Article
C2 - 15961672
AN - SCOPUS:27544493942
VL - 68
SP - 1496
EP - 1503
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 5
ER -