State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China.
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, People's Republic of China.
Carcinogenesis. 2018 Oct 8;39(10):1292-1303. doi: 10.1093/carcin/bgy004.
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 from Scutellariae 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 vivo studies 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.
肿瘤坏死因子-α（TNFα）是一种复杂的细胞因子，通过一种尚未完全了解的机制参与急性髓系白血病（AML）细胞的增殖和分化。机制研究表明，TNFα诱导 PI3K 亚基 p85α与 N 端截断的核受体 RXRα（tRXRα）蛋白结合，并激活 AKT。激活的 PI3K/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 NF-κB（NF-κB）的激活，该因子被证明可促进细胞增殖。本研究表明，从黄芩根中分离得到的天然化合物白杨素 A 可使白血病细胞对 TNFα敏感，并显著增强 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。白杨素 A 通过抑制 NB4 和 HL-60 耐药细胞中 tRXRα的表达，可抑制 PI3K/AKT 通路的激活。此外，我们发现白杨素 A 可抑制 NF-κB 的激活，通过 EMSA 在这两种 AML 细胞系中证实 TNFα 引起的 DNA 结合活性受到抑制。此外，体内研究表明，在 NOD/SCID 小鼠中用 TNFα联合白杨素 A 治疗可减少原代 AML 细胞移植瘤中的 AML 细胞群并延长其存活时间。总的来说，我们的研究结果表明，白杨素 A 能够抑制 TNFα对 AML 治疗的负面影响，表明白杨素 A 与 TNFα 的联合应用有可能延缓异常白血病细胞的生长或消除它们，从而为 AML 治疗提供一种有前景的策略。
