Dissection of mechanisms of Chinese medicinal formula Realgar- Indigo naturalis as an effective treatment for promyelocytic leukemia

作者：Lan Wang, Guang‐Biao Zhou, Ping Liu, Jun-Hong Song, Yang Liang, Xiao-Jing Yan, Fang Xu, Bingshun Wang, Jian‐Hua Mao, Zhi-Xiang Shen, Sai-Juan Chen, Chen Zhu · 发表于：Proceedings of the National Academy of Sciences · 年份：2008 · DOI：10.1073/pnas.0712365105 · 被引用次数：740 · 研究领域：Retinoids in leukemia and cellular processes、Acute Myeloid Leukemia Research、Histone Deacetylase Inhibitors Research

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 alpha (RARalpha) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G(1)/G(0) 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-RARalpha degradation and therapeutic efficacy. Our data also indicate A as the principal compone...