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Molecular Pharmacology

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Research ArticleArticle

Selective Effects of the Anticancer Drug Yondelis (ET-743) on Cell-Cycle Promoters

Mario Minuzzo, Michele Ceribelli, Marià Pitarque-Martì, Serena Borrelli, Eugenio Erba, Alberto diSilvio, Maurizio D'Incalci and Roberto Mantovani
Molecular Pharmacology November 2005, 68 (5) 1496-1503; DOI: https://doi.org/10.1124/mol.105.013615
Mario Minuzzo
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Michele Ceribelli
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Marià Pitarque-Martì
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Serena Borrelli
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Eugenio Erba
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Alberto diSilvio
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Maurizio D'Incalci
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Roberto Mantovani
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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.

  • Received April 12, 2005.
  • Accepted June 16, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (5)
Molecular Pharmacology
Vol. 68, Issue 5
1 Nov 2005
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Research ArticleArticle

Selective Effects of the Anticancer Drug Yondelis (ET-743) on Cell-Cycle Promoters

Mario Minuzzo, Michele Ceribelli, Marià Pitarque-Martì, Serena Borrelli, Eugenio Erba, Alberto diSilvio, Maurizio D'Incalci and Roberto Mantovani
Molecular Pharmacology November 1, 2005, 68 (5) 1496-1503; DOI: https://doi.org/10.1124/mol.105.013615

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Research ArticleArticle

Selective Effects of the Anticancer Drug Yondelis (ET-743) on Cell-Cycle Promoters

Mario Minuzzo, Michele Ceribelli, Marià Pitarque-Martì, Serena Borrelli, Eugenio Erba, Alberto diSilvio, Maurizio D'Incalci and Roberto Mantovani
Molecular Pharmacology November 1, 2005, 68 (5) 1496-1503; DOI: https://doi.org/10.1124/mol.105.013615
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