title: Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters.
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.
authors.affiliation: Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Via Celoria 26, 20133 Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Minuzzo
authors.forename: Michele
authors.initials: M
authors.lastname: Ceribelli
authors.forename: Marià
authors.initials: M
authors.lastname: Pitarque-Martì
authors.forename: Serena
authors.initials: S
authors.lastname: Borrelli
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Alberto
authors.initials: A
authors.lastname: DiSilvio
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Roberto
authors.initials: R
authors.lastname: Mantovani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D023081:CCAAT-Binding Factor; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004247:DNA; D000077606:Trabectedin