College of Pharmacy and The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, and State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China.
J Med Chem. 2012 Oct 25;55(20):8757-69. doi: 10.1021/jm301064b. Epub 2012 Oct 11.
Small molecules that can selectively target cancer stem cells (CSCs) remain rare currently and exhibit no common structural features. Here we report a series of guaianolide sesquiterpene lactones (GSLs) and their derivatives that can selectively eradicate acute myelogenous leukemia (AML) stem or progenitor cells. Natural GSL compounds arglabin, an anticancer clinical drug, and micheliolide (MCL), are able to reduce the proportion of AML stem cells (CD34⁺CD38⁻) in primary AML cells. Targeting of AML stem cells is further confirmed by a sharp reduction of colony-forming units of primary AML cells upon MCL treatment. Moreover, DMAMCL, the dimethylamino Michael adduct of MCL, slowly releases MCL in plasma and in vivo and demonstrates remarkable therapeutic efficacy in the nonobese diabetic/severe combined immunodeficiency AML models. These findings indicate that GSL is an ample source for chemical agents against AML stem or progenitor cells and that GSL is potentially highly useful to explore anti-CSC approaches.
目前，能够选择性靶向肿瘤干细胞（CSC）的小分子仍然很少，并且没有共同的结构特征。在这里，我们报告了一系列愈创木烷型倍半萜内酯（GSL）及其衍生物，它们可以选择性地根除急性髓系白血病（AML）干细胞或祖细胞。天然 GSL 化合物阿格拉宾、抗癌临床药物和 Micheliaolide（MCL）能够降低原代 AML 细胞中 AML 干细胞（CD34 ⁺ CD38 ⁻ ）的比例。MCL 处理后，原代 AML 细胞集落形成单位的明显减少进一步证实了对 AML 干细胞的靶向作用。此外，MCL 的二甲氨基迈克尔加成物 DMAMCL 在血浆和体内缓慢释放 MCL，并在非肥胖型糖尿病/严重联合免疫缺陷 AML 模型中显示出显著的治疗效果。这些发现表明 GSL 是对抗 AML 干细胞或祖细胞的化学试剂的丰富来源，并且 GSL 很可能非常有助于探索抗 CSC 方法。
