Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation
Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation
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DOI：
10.1073/pnas.97.12.6775
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发表时间：
2000-06-06
影响因子：
11.1
通讯作者：
Scotto, KW
中科院分区：
文献类型：
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作者：
Jin, S;Gorfajn, B;Scotto, KW
海鞘素743（Ecteinascidin 743，ET-743）是一种非常有前途的海洋抗肿瘤药物，目前处于II期临床试验中，已被证明在体外干扰小沟相互作用转录因子（特别是NF-γ）与其同源启动子元件的结合。我们已经表明，NF-Y是一个中央调解人的P糖蛋白基因（MDR 1）的转录激活的各种诱导剂和NF-Y的功能招募组蛋白乙酰转移酶PCAF的MDR 1启动子。在本研究中，我们测试了ET-743是否可以阻断通过NF-Y/PCAF复合物介导其作用的药物对MDR 1启动子的激活。我们报告说，生理相关浓度的ET-743废除转录激活的内源性MDR 1基因和MDR 1报告构建的组蛋白去乙酰化酶抑制剂，以及通过紫外线，与组成性MDR 1转录的影响最小。值得注意的是，这种抑制不会改变由组蛋白脱乙酰酶抑制剂诱导的启动子相关的组蛋白超乙酰化，表明NF-γ/PCAF结合下游的体内分子靶点。因此，ET-743是一类独特的转录靶向化疗药物的原型，可能是治疗多药耐药肿瘤的有效佐剂。
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.