RT Journal Article
SR Electronic
T1 Selective Effects of the Anticancer Drug Yondelis (ET-743) on Cell-Cycle Promoters
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1496
OP 1503
DO 10.1124/mol.105.013615
VO 68
IS 5
A1 Mario Minuzzo
A1 Michele Ceribelli
A1 Marià Pitarque-Martì
A1 Serena Borrelli
A1 Eugenio Erba
A1 Alberto diSilvio
A1 Maurizio D'Incalci
A1 Roberto Mantovani
YR 2005
UL http://molpharm.aspetjournals.org/content/68/5/1496.abstract
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.