组蛋白去乙酰化酶抑制剂调节肿瘤细胞多药耐药性的机制

Mechanism of regulating multidrug resistances by histone deacetylase inhibitors in tumor cells

肿瘤的多药耐药性往往导致化疗失败,其主要原因是外排抗肿瘤药物的ABC蛋白过度表达所致。文中以研究较多的mdr-1基因的表达调控为例,综述从表观遗传修饰方面克服多药耐药性的研究进展。组蛋白去乙酰化酶抑制剂不仅具有良好的抗肿瘤活性,对肿瘤耐药细胞也无交叉耐药性,通过诱导耐药细胞凋亡而起作用。在mdr-1基因的活化表达过程中,需要其启动子区域DNA的去甲基化和组蛋白乙酰化的协同作用。目前的研究表明:以表观遗传修饰为药物靶标,发展克服多药耐药性药物具有诱人的前景。

The muhidrug resistance in tumors often leads to failure of tumor chemotherapy as most tumors overexpress ATP-binding cassette （ABC） proteins that can pump out of antitumor drugs from the cells. In this article, we reviewed the progress of overcoming muhidrug resistances, and aimed at the regulation of mdr-1 gene ex- pression via epigenetic modification. Histone deacetylase inhibitors exhibit favorable anti-tumor activity and no cross resistance to muhidrug-resistant tumor ceils by inducing tumor ceils to apoptosis. Synergistic actions of DNA dem＇ ethylation and histone acetylation in the promoter region are needed in the activation of mdr-1 gene. A lot of current researches show that it will have potential prospects to develop antitumor agents targeted to epigenetic modifications for overcoming multidrug resistances.