Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia
Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia
复制标题
雄黄青黛中药方剂治疗早幼粒细胞白血病的作用机制解析
DOI：
10.1073/pnas.0712365105
复制
发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Chen, Zhu
中科院分区：
文献类型：
--
作者：
Wang, Lan;Zhou, Guang-Biao;Chen, Zhu
为了提高疗效和减少副作用，中医师根据临床经验开出植物种类/矿物质的组合，称为配方。已记录了近10万个公式，但大多数的工作机制仍然未知。在试图解决目前的生物医学方法的公式可能的有益效果，我们使用雄黄靛蓝天然配方（RIF），这已被证明是非常有效的治疗人类急性早幼粒细胞白血病（APL）作为一个模型。RIF的主要成分是雄黄、靛蓝和丹参，分别以四硫化四砷（A）、靛玉红（I）和丹参酮IIA（T）为主要活性成分。在这里，我们报告ATI组合产生协同作用，在治疗小鼠APL模型在体内和在诱导APL细胞分化在体外。与单药或双药相比，ATI通过击中多个靶点，导致早幼粒细胞白血病（PML）-维甲酸受体α（RARα）癌蛋白的泛素化/降解增强，髓样分化调节因子的重编程增强，APL细胞中G1/G 0阻滞增强。此外，ATI增强水甘油孔蛋白9的表达，促进A转运到APL细胞中，从而增强A介导的PML-RARα降解和治疗功效。我们的数据还表明，A作为配方的主要成分，而T和I作为辅助成分。因此，从分子、细胞和机体水平上剖析临床有效方剂的作用机制，可能是发掘传统医学价值的一个很好的策略。
To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G1/G0 arrest in APL cells through hitting multiple targets compared with the effects of mono- or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RARα degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.