Liu Jun, Xu Chun-Yan, Cai Shi-Zhong, Zhou Yue, Li Jing, Jiang Rong, Wang Ya-Ping
Histology and Embryology, Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China E-mail :
Asian Pac J Cancer Prev. 2014 Jan;14(11):6549-56. doi: 10.7314/apjcp.2013.14.11.6549.
Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML CD34+CD38? cell proliferation in vitro culture in a dose-dependent manner while sparing normal hematopoietic stem and progenitor cells at physiologically achievable concentrations. Furthermore, ASP exerted cytotoxic effects on AML K562 cells, especially LSC-enriched CD34+CD38? cells. Colony formation assays further showed that ASP significantly suppressed the formation of colonies derived from AML CD34+CD38? cells but not those from normal CD34+CD38? cells. Examination of the underlying mechanisms revealed that ASP induced CD34+CD38? cell senescence, which was strongly associated with a series of characteristic events, including up-regulation of p53, p16, p21, and Rb genes and changes of related cell cycle regulation proteins P16, P21, cyclin E and CDK4, telomere end attrition as well as repression of telomerase activity. On the basis of these findings, we propose that ASP represents a potentially important agent for leukemia stem cell-targeted therapy.
白血病干细胞（LSCs）在白血病的起始、进展和复发中起重要作用，因此是治疗干预的关键靶点。因此，探索直接靶向LSCs的新治疗策略用于急性髓性白血病（AML）治疗迫在眉睫。我们在此表明，当归多糖（ASP）是当归中的主要活性成分，能在体外培养中以剂量依赖方式有效抑制人AML CD34+CD38⁻细胞增殖，同时在生理可达到的浓度下不影响正常造血干细胞和祖细胞。此外，ASP对AML K562细胞，尤其是富含LSC的CD34+CD38⁻细胞具有细胞毒性作用。集落形成试验进一步表明，ASP显著抑制AML CD34+CD38⁻细胞形成的集落，但不影响正常CD34+CD38⁻细胞形成的集落。对潜在机制的研究表明，ASP诱导CD34+CD38⁻细胞衰老，这与一系列特征性事件密切相关，包括p53、p16、p21和Rb基因上调以及相关细胞周期调节蛋白P16、P21、细胞周期蛋白E和CDK4的变化、端粒末端磨损以及端粒酶活性的抑制。基于这些发现，我们提出ASP是一种潜在的重要白血病干细胞靶向治疗药物。
