Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
The Center for Advanced Insect Research Promotion (CAIRP), Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
Int J Mol Sci. 2017 Dec 2;18(12):2603. doi: 10.3390/ijms18122603.
Quinacrine has been used for therapeutic drugs in some clinical settings. In the present study, we demonstrated that quinacrine decreased the expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor (TNF)-α and interleukin-1 (IL-1) α in human lung adenocarcinoma A549 cells. Quinacrine inhibited ICAM-1 mRNA expression and nuclear factor κB (NF-κB)-responsive luciferase reporter activity following a treatment with TNF-α and IL-1α. In the NF-κB signaling pathway, quinacrine did not markedly affect the TNF-α-induced degradation of the inhibitor of NF-κB or the TNF-α-induced phosphorylation of the NF-κB subunit, p65, at Ser-536 and its subsequent translocation to the nucleus. In contrast, a chromatin immunoprecipitation assay showed that quinacrine prevented the binding of p65 to the ICAM-1 promoter following TNF-α stimulation. Moreover, TNF-α and the Fas ligand effectively reduced the viability of A549 cells in the presence of quinacrine only. Quinacrine down-regulated the constitutive and TNF-α-induced expression of c-FLIP and Mcl-1 in A549 cells. These results revealed that quinacrine inhibits ICAM-1 transcription by blocking the DNA binding of p65 and sensitizes A549 cells to TNF-α and the Fas ligand.
盐酸奎宁曾被用于一些临床环境下的治疗药物。在本研究中，我们证明了盐酸奎宁可降低肿瘤坏死因子（TNF）-α和白细胞介素-1（IL-1）α诱导的人肺腺癌细胞 A549 细胞中细胞间黏附分子-1（ICAM-1）的表达。盐酸奎宁可抑制 TNF-α和 IL-1α处理后 ICAM-1mRNA 表达和核因子 κB（NF-κB）反应性荧光素酶报告基因活性。在 NF-κB 信号通路中，盐酸奎宁对 TNF-α诱导的 NF-κB 抑制剂降解或 TNF-α诱导的 NF-κB 亚基 p65 丝氨酸 536 磷酸化及其随后向核内转位没有明显影响。相比之下，染色质免疫沉淀分析表明，盐酸奎宁可阻止 TNF-α刺激后 p65 与 ICAM-1 启动子的结合。此外，只有在存在盐酸奎宁的情况下，TNF-α和 Fas 配体才能有效降低 A549 细胞的活力。盐酸奎宁可下调 A549 细胞中 c-FLIP 和 Mcl-1 的组成性和 TNF-α诱导性表达。这些结果表明，盐酸奎宁通过阻断 p65 的 DNA 结合抑制 ICAM-1 转录，并使 A549 细胞对 TNF-α和 Fas 配体敏感。
