Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743.
Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated from the tunicate Ecteinascidia turbinata currently under phase II clinical trials for its potent anticancer activity. ET-743 binds DNA in the minor groove and forms covalent adducts with some sequence specificity. It selectively inhibits in vitro binding of the CCAAT box factor NF-Y. In this study, we assayed ET-743 function in vivo on the HSP70 promoter. On heat induction, the drug blocks transcription rapidly at pharmacological concentrations and in a CCAAT-dependent manner, whereas the activity of the CCAAT-less simian virus 40 promoter is not affected. The effect is exerted at the mRNA level. The distamycin-like alkylating tallimustine is inactive in these assays. Binding of NF-Y and of the heat-shock factor is normal in ET-743-treated cells. Run-on analysis of several endogenous genes further proves that the drug has rapid, profound, and selective negative effects on transcription. Thus, this marine-derived compound is a promoter-specific, transcription-interfering agent.
Minuzzo
M
M
Dipartimento di Genetica e di Biologia dei Microrganismi, Università degli Studi di Milano, Via Celoria 26, 20133 Milano, Italy.
Marchini
S
S
Broggini
M
M
Faircloth
G
G
D'Incalci
M
M
Mantovani
R
R
D016475:3T3 Cells; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D011401:Promoter Regions, Genetic; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D015533:Transcriptional Activation / Q000187:drug effects*
D018906:Antineoplastic Agents, Alkylating; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004149:Dioxoles; D018840:HSP70 Heat-Shock Proteins; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004247:DNA; D000077606:Trabectedin