Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters.
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.
Minuzzo
Mario
M
Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Via Celoria 26, 20133 Milano, Italy.
Ceribelli
Michele
M
Pitarque-Martì
Marià
M
Borrelli
Serena
S
Erba
Eugenio
E
DiSilvio
Alberto
A
D'Incalci
Maurizio
M
Mantovani
Roberto
R
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
D000970:Antineoplastic Agents; D023081:CCAAT-Binding Factor; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004247:DNA; D000077606:Trabectedin