Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation.
Ecteinascidin 743 (ET-743), a highly promising marine-based antitumor agent presently in phase II clinical trials, has been shown to interfere with the binding of minor-groove-interacting transcription factors, particularly NF-Y, with their cognate promoter elements in vitro. We have shown that NF-Y is a central mediator of activation of transcription of the human P glycoprotein gene (MDR1) by a variety of inducers and that NF-Y functions by recruiting the histone acetyltransferase PCAF to the MDR1 promoter. In the present study, we tested whether ET-743 could block activation of the MDR1 promoter by agents that mediate their effect through the NF-Y/PCAF complex. We report that physiologically relevant concentrations of ET-743 abrogate transcriptional activation of both the endogenous MDR1 gene and MDR1 reporter constructs by the histone deacetylase inhibitors as well as by UV light, with minimal effect on constitutive MDR1 transcription. Notably, this inhibition does not alter the promoter-associated histone hyperacetylation induced by histone deacetylase inhibitors, suggesting an in vivo molecular target downstream of NF-Y/PCAF binding. ET-743 is therefore the prototype for a distinct class of transcription-targeted chemotherapeutic agents and may be an efficacious adjuvant to the treatment of multidrug-resistant tumors.
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Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center and the Weill Graduate School of Medical Sciences of Cornell University, 1275 York Avenue, New York, NY 10021, USA.
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000107:Acetylation; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018906:Antineoplastic Agents, Alkylating; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004149:Dioxoles; D006877:Hydroxamic Acids; D007546:Isoquinolines; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; C012589:trichostatin A; D004247:DNA; D000077606:Trabectedin