Dihydroartemisinin Increases the Sensitivity of Photodynamic Therapy Via NF-κB/HIF-1α/VEGF Pathway in Esophageal Cancer Cell in vitro and in vivo
Dihydroartemisinin Increases the Sensitivity of Photodynamic Therapy Via NF-κB/HIF-1α/VEGF Pathway in Esophageal Cancer Cell in vitro and in vivo
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DOI：
10.1159/000492541
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Bai, Yuxian
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文献类型：
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作者：
Li, Yanjing;Sui, Hong;Bai, Yuxian
背景/目标：光动力疗法（PDT）虽然能解除食管梗阻，延长食管癌患者的生存时间，但在许多癌症中可诱导核因子-κ B（NF-κ B）活化，对PDT起负面作用。双氢青蒿素（DHA）是青蒿素最有效的衍生物，可增强PDT对食管癌细胞的作用。然而，其机制尚不清楚。研究方法：我们产生了表达NF-κ B抑制剂I κ B α的超阻遏物形式的稳定细胞系和具有慢病毒载体介导的HIF-1 α基因沉默的细胞系。食管异种移植瘤通过皮下注射Eca 109细胞到BALB/c裸鼠中来产生。分析了四个治疗组：对照组、单独光敏剂组、单独光组和PDT组。采用电泳迁移率改变法检测NF-κ B表达，实时荧光定量PCR检测缺氧诱导因子α（HIF-1 α）和血管内皮生长因子（VEGF），Western blot检测NF-κ B、HIF-1 α和VEGF蛋白，免疫组化检测Ki-67、HIF-1 α、VEGF和NF-κ B蛋白。结果：PDT能增强NF-κ B B活性，促进HIF-1 α和VEGF基因表达。相比之下，DHA组，特别是DHA和PDT联合治疗组，消除了这种作用。联合治疗在体外和体内显著抑制肿瘤生长。NF-κ B活性和HIF-1 α表达在I κ B α稳定表达组中也降低，而前者在HIF-1 α沉默细胞中没有变化。结论：DHA可能通过抑制NF-κ B B/HIF-1 α/VEGF信号通路，增强食管癌细胞对PDT的敏感性。(C)2018作者（S）由S发布。Karger AG，巴塞尔。
Background/Aims: Although photodynamic therapy (PDT) can relieve esophageal obstruction and prolong survival time of patients with esophageal cancer, it can induce nuclear factor-kappa B (NF-kappa B) activation in many cancers, which plays a negative role in PDT. Dihydroartemisinin (DHA), the most potent artemisinin derivative, can enhance the effect of PDT on esophageal cancer cells. However, the mechanism is still unclear. Methods: We generated stable cell lines expressing the super-repressor form of the NF-kappa B inhibitor I kappa B alpha and cell lines with lentivirus vector-mediated silencing of the HIF-1 alpha gene. Esophageal xenograft tumors were created by subcutaneous injection of Eca109 cells into BALB/c nude mice. Four treatment groups were analyzed: a control group, photosensitizer alone group, light alone group, and PDT group. NF-kappa B expression was detected by an electrophoretic mobility shift assay, hypoxiainducible factor alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) by real-time PCR, NF-kappa B, HIF-1 alpha, and VEGF protein by western blot, and Ki-67, HIF-1 alpha, VEGF, and NF-kappa B protein by immunohistochemistry. Results: PDT increased NF-kappa B activity and the gene expression of HIF-1 alpha and VEGF in vitro and in vivo. In contrast, the DHA groups, particularly the combined DHA and PDT treatment group, abolished the effect. The combined treatment significantly inhibited tumor growth in vitro and in vivo. NF-kappa B activity and HIF-1 alpha expression were also reduced in the stable I kappa B alpha expression group, whereas the former showed no change in HIF-1 alpha-silenced cells. Conclusion: DHA might increase the sensitivity of esophageal cancer cells to PDT by inhibiting the NF-kappa B/HIF-1 alpha/VEGF pathway. (C) 2018 The Author(s) Published by S. Karger AG, Basel.