Oroxylin A,a natural compound, mitigates the negative effects of TNFα-treated acute myelogenous leukemia cells
Oroxylin A,a natural compound, mitigates the negative effects of TNFα-treated acute myelogenous leukemia cells
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Oroxylin A 是一种天然化合物，可减轻 TNFα 治疗的急性髓性白血病细胞的负面影响
DOI：
10.1093/carcin/bgy004
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发表时间：
2018
期刊：
影响因子：
4.7
通讯作者：
Hui Hui
中科院分区：
文献类型：
--
作者：
Li Hui;Lu Na;Yu Xiaoxuan;Liu Xiao;Hu Po;Zhu Yu;Shen Le;Xu Jingyan;Li Zhiyu;Guo Qinglong;Hui Hui
肿瘤坏死因子α（tumor necrosis factor alpha，TNFα）是一种复杂的细胞因子，参与急性髓性白血病（acute myelogenous leukemia，AML）细胞的增殖和分化，其机制尚不清楚。机制研究表明，TNFα诱导PI 3 K亚基p85α与N端截短核受体RXRα（tRXRα）蛋白结合，并激活AKT。活化的PI 3 K/AKT通路通过上调c-Myc负调控AML细胞的分化。此外，TNFα还诱导核转录因子κB（NF-κB）活化，NF-κB是一种核转录因子，可促进细胞增殖。本文研究表明，从甘草中提取的天然化合物木脂素A能使白血病细胞对TNFα敏感，并能显著增强TNFα诱导的AML细胞（包括人白血病细胞系和原代AML细胞）的生长抑制和分化。在NB 4和HL-60耐药细胞中，oroxylin A可通过抑制tRXRα的表达来抑制PI 3 K/AKT通路的激活。EMSA结果显示，在上述两种AML细胞株中，oroxylin A可抑制NF-κB的活化和TNFα的DNA结合活性。此外，体内研究显示，在具有原代AML细胞异种移植物的NOD/SCID小鼠中，用木脂素A与TNFα组合治疗减少AML细胞群并延长存活。总体而言，我们的结果表明，oroxylin A能够抑制TNFα对AML治疗的负面影响，这表明oroxylin A和TNFα的组合具有延迟生长或消除异常白血病细胞的潜力，因此代表了AML治疗的有希望的策略。
Tumor necrosis factor alpha (TNFα) is a complicated cytokine which is involved in proliferation and differentiation of acute myelogenous leukemia (AML) cells through a poorly understood mechanism. Mechanistic studies indicate that TNFα induced binding of PI3K subunit p85α to N-terminal truncated nuclear receptor RXRα (tRXRα) proteins, and activated AKT. The activated PI3K/AKT pathway negatively regulated differentiation of AML cells through the upregulation of c-Myc. In addition, TNFα also induced activation of nuclear factor κB (NF-κB), a nuclear transcription factor which was shown to promote cell proliferation. The present study demonstrates that oroxylin A, a natural compound isolated fromScutellariae radix, sensitizes leukemia cells to TNFα and markedly enhances TNFα-induced growth inhibition and differentiation of AML cell including human leukemia cell lines and primary AML cells. Activation of PI3K/AKT pathway could be inhibited by oroxylin A through inhibiting expression of tRXRα in NB4 and HL-60-resistant cells. Furthermore, we found that oroxylin A inhibited the activation of NF-κB and the DNA binding activity by TNFα proved by EMSA in these two AML cell lines. Moreover,in vivostudies showed that treatment with oroxylin A in combination with TNFα decreased AML cell population and prolonged survival in NOD/SCID mice with xenografts of primary AML cells. Overall, our results indicate that oroxylin A is able to inhibit the negative effects of TNFα for AML therapy, suggesting that combination of oroxylin A and TNFα have the potential to delay growth or eliminate the abnormal leukemic cells, thus representing a promising strategy for AML treatment.