Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation
Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation
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二硫化砷与磷酸肌醇3激酶抑制剂PI-103协同作用，通过诱导分化根除急性髓系白血病干细胞
DOI：
10.1093/carcin/bgr176
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发表时间：
2011-10-01
期刊：
影响因子：
4.7
通讯作者：
Zhou, Jianfeng
中科院分区：
文献类型：
--
作者：
Hong, Zhenya;Xiao, Min;Zhou, Jianfeng
虽然在急性早幼粒细胞白血病（APL）中取得了巨大的临床成功，但分化剂的成功尚未在非APL白血病中重现。砷临床成功的一个关键障碍是，它不足以通过单独靶向白血病细胞分化途径在生理可耐受浓度下实现临床益处。我们探索了一种新的联合方法，以增强砷在非APL白血病中根除白血病干细胞（LSC）。在本研究中，磷脂酰肌醇3-激酶/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）磷酸化增强As 2S 2暴露后，白血病细胞系和干/祖细胞，但不是在脐带血单核细胞（CBMCs）。PI 3 K/mTOR双重抑制剂碘化丙啶-103可有效抑制As 2 S2对PI 3 K/AKT/mTOR通路的瞬时激活。在体外和体内研究了对非APL白血病细胞的协同杀伤和诱导分化作用。使用非肥胖糖尿病/严重联合免疫缺陷小鼠模型确定非APL LSC的根除。我们发现As 2S 2/PI-103联合治疗具有强烈的协同作用，可以杀死非APL白血病细胞并促进其体外分化。此外，组合的As 2S 2/PI-103治疗有效地减少了白血病细胞再增殖，并通过诱导分化部分根除了非APL LSC，同时保留了正常的造血干细胞。总之，这些发现表明PI 3 K/AKT/mTOR通路的诱导可以提供保护性应答以抵消As 2S 2的抗肿瘤功效。靶向PI 3 K/AKT/mTOR通路与As 2S 2的组合可以被开发为增强非APL LSC的分化和杀伤的新策略。
Although dramatic clinical success has been achieved in acute promyelocytic leukemia (APL), the success of differentiating agents has not been reproduced in non-APL leukemia. A key barrier to the clinical success of arsenic is that it is not potent enough to achieve a clinical benefit at physiologically tolerable concentrations by targeting the leukemia cell differentiation pathway alone. We explored a novel combination approach to enhance the eradication of leukemia stem cells (LSCs) by arsenic in non-APL leukemia. In the present study, phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin (mTOR) phosphorylation was strengthened after As2S2 exposure in leukemia cell lines and stem/progenitor cells, but not in cord blood mononuclear cells (CBMCs). propidium iodide-103, the dual PI3K/mTOR inhibitor, effectively inhibited the transient activation of the PI3K/AKT/mTOR pathway by As2S2. The synergistic killing and differentiation induction effects on non-APL leukemia cells were examined both in vitro and in vivo. Eradication of non-APL LSCs was determined using the nonobese diabetic/severe combined immunodeficiency mouse model. We found that a combined As2S2/PI-103 treatment synergized strongly to kill non-APL leukemia cells and promote their differentiation in vitro. Furthermore, the combined As2S2/PI-103 treatment effectively reduced leukemia cell repopulation and eradicated non-APL LSCs partially via induction of differentiation while sparing normal hematopoietic stem cells. Taken together, these findings suggest that induction of the PI3K/AKT/mTOR pathway could provide a protective response to offset the antitumor efficacy of As2S2. Targeting the PI3K/AKT/mTOR pathway in combination with As2S2 could be exploited as a novel strategy to enhance the differentiation and killing of non-APL LSCs.