Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells.
Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells.
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Alantolactone 选择性消融急性髓性白血病干细胞和祖细胞
DOI：
10.1186/s13045-016-0327-5
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发表时间：
2016-09-22
影响因子：
28.5
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Ding Y;Gao H;Zhang Y;Li Y;Vasdev N;Gao Y;Chen Y;Zhang Q
研究背景急性髓细胞白血病（AML）患者预后差的主要原因是白血病干细胞（LSC）难以用常规治疗清除，并导致复发。因此，临床上迫切需要能够选择性靶向LSC并避免耐药的新的治疗策略。然而，只有少数小分子已被报道显示anti-LSCs activity.MethodsThe本研究的目的是确定土木香内酯作为新的代理，可以消融急性髓系白血病干细胞和祖细胞从AML患者标本和评估的抗癌活性土木香内酯在体外和体内。ResultsThe本研究是第一次证明土木香内酯，一个突出的桉烷型倍半萜内酯，可以特异性消融AML患者标本中的LSC。此外，与常规化疗药物阿糖胞苷（Ara-C）相比，土木香内酯显示出上级的白血病细胞毒性作用，同时保留正常造血细胞。土木香内酯通过抑制NF-kB及其下游靶蛋白以剂量依赖性方式诱导细胞凋亡。DMA-alantolactone，alantolactone的水溶性前体药物，可以抑制肿瘤生长在vivo.ConclusionsBased on these结果，我们提出，alantolactone可能代表一种新的LSCs靶向治疗和桉烷型倍半萜内酯提供了一个新的骨架药物发现对抗LSCs剂。
BackgroundThe poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity.MethodsThe aim of the present study was to identify alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of alantolactone in vitro and in vivo.ResultsThe present study is the first to demonstrate that alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-alantolactone, a water-soluble prodrug of alantolactone, could suppress tumor growth in vivo.ConclusionsBased on these results, we propose that alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents.
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