Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl,2-methyl,1,2,4-thiadiazolidine,3,5-dione (TDZD-8)
Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl,2-methyl,1,2,4-thiadiazolidine,3,5-dione (TDZD-8)
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DOI：
10.1182/blood-2007-05-088815
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Jordan, Craig T.
中科院分区：
文献类型：
--
作者：
Guzman, Monica L.;Li, Xiaojie;Jordan, Craig T.
白血病被认为是由恶性干细胞引起的，急性和慢性髓性白血病（AML和CML）和急性淋巴细胞白血病（ALL）都有这种描述。白血病干细胞（LSCs）对目前的化疗相对耐药，可能导致疾病复发和进展。因此，确定能够有效根除LSCs的药物是一个重要的优先事项。在本研究中，我们研究了化合物TDZD-8的抗白血病活性。对原发性AML、原细胞危象性CML （bcCML）、ALL和慢性淋巴细胞白血病（CLL）标本的分析显示，TDZD-8治疗可快速诱导细胞死亡。此外，对于髓系白血病，细胞毒性被观察到表型原始细胞、体外集落形成祖细胞和异种移植实验定义的LSCs。相反，对正常造血干细胞和祖细胞没有观察到明显的毒性。值得注意的是，在TDZD-8暴露后2小时或更短时间内，细胞死亡往往很明显。细胞和分子研究表明，TDZD-8诱导细胞死亡的机制包括膜完整性的快速丧失、游离硫醇的消耗以及PKC和FLT3信号通路的抑制。我们得出结论，TDZD-8使用一种独特的、以前未知的机制来快速靶向白血病细胞，包括恶性干细胞和祖细胞群体。
Leukemia is thought to arise from malignant stem cells, which have been described for acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia (ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Consequently, the identification of drugs that can efficiently eradicate LSCs is an important priority. In the present study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In contrast, no significant toxicity was observed for normal hematopoietic stem and progenitor cells. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations.