MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML.
MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML.
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作者：
雷公藤甲素从雷公藤中分离出来，通过抑制RNA合成和NF-κB活性，有效诱导多种恶性细胞凋亡。先前，我们发现雷公藤甲素通过线粒体介导的途径促进急性髓性白血病（AML）细胞的凋亡，部分原因是通过降低抗凋亡蛋白XIAP和Mcl-1的水平。MRx102是雷公藤甲素衍生物，目前处于临床前开发阶段。在这里，我们发现MRx102有效地促进了AML细胞系的凋亡，OCI-AML3和MV4-11细胞48小时的EC50值分别为14.5±0.6 nM和37.0±0.9 nM。在低纳摩尔浓度下，MRx102也能诱导来自AML患者的大量CD34+祖细胞和更重要的CD34+CD38 -干细胞/祖细胞凋亡，即使这些细胞与骨髓间充质基质细胞共培养也是如此。MRx102降低OCI-AML3细胞中XIAP和Mcl-1蛋白水平，抑制RNA合成。在体内，MRx102显著降低了携带Ba/F3-ITD细胞的NOD/SCID小鼠的白血病负担，延长了存活时间。总之，我们证明了MRx102在体外和体内都具有强大的抗白血病活性，具有消除AML干细胞/祖细胞和克服白血病细胞微环境保护的潜力，值得临床研究。
Triptolide, isolated from the herb Tripterygium wilfordii, has been shown to potently induce apoptosis in various malignant cells by inhibiting RNA synthesis and NF-κB activity. Previously, we showed that triptolide promotes apoptosis in acute myeloid leukemia (AML) cells via the mitochondria-mediated pathway, in part by decreasing levels of the anti-apoptotic proteins XIAP and Mcl-1. MRx102 is a triptolide derivative currently in preclinical development. Here, we show that MRx102 potently promoted apoptosis in AML cell lines, with EC50 values of 14.5 ± 0.6 nM and 37.0 ± 0.9 nM at 48 hours for OCI-AML3 and MV4-11 cells, respectively. MRx102, at low nanomolar concentrations, also induced apoptosis in bulk, CD34+ progenitor, and more importantly CD34+CD38− stem/progenitor cells from AML patients, even when they were protected by co-culture with bone marrow mesenchymal stromal cells. MRx102 decreased XIAP and Mcl-1 protein levels and inhibited RNA synthesis in OCI-AML3 cells. In vivo, MRx102 greatly decreased leukemia burden and increased survival time in NOD/SCID mice harboring Ba/F3-ITD cells. Collectively, we demonstrated that MRx102 has potent antileukemic activity both in vitro and in vivo, has the potential to eliminate AML stem/progenitor cells and overcome microenvironmental protection of leukemic cells, and warrants clinical investigation.
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