大黄素增强砷剂对食道癌细胞的促凋亡作用

Emodin-Enhanced Arsenic-Induced Apoptosis on Esophageal Tumor Cells

目的在体外培养的食道癌细胞株和食道癌细胞的体内移植瘤动物模型上,考察天然物质大黄素通过提高活性氧水平增强砷剂(As2O3)诱导凋亡的作用,同时探讨大黄素造成的氧化还原状态改变对凋亡与抗凋亡信号转导机制的影响。方法在食道癌细胞株上联合应用大黄素与As2O3,检测细胞凋亡率、线粒体细胞色素C释放、生存相关转录因子NF-κB活性及下游抗凋亡蛋白survivin表达;在食道癌移植瘤动物模型上应用不同剂量大黄素与As2O3腹腔注射化疗,化疗后检测瘤体质量,瘤组织切片上检测凋亡、NF-κB入核和下游抗凋亡蛋白survivin表达。结果大黄素增强As2O3诱导的凋亡,促进线粒体细胞色素C释放,抑制NF-κB促转录活性;大黄素与As2O3合用增强裸鼠移植瘤凋亡,抑制NF-κB入核,并下调survivin表达。结论大黄素能够促进体内外食道癌细胞的凋亡,机制涉及增强促凋亡信号转导和抑制抗凋亡信号转导,提示了大黄素的作用机制和应用的可行性。

Objective To determine if natural emodin can enhance arsenic-induced apoptosis via increasing reactive oxygen species （ROS） on cultured esophageal tumor cells in vitro and transplanted neoplasms with esophageal tumor cells in vivo, and to demonstrate the effect of emodin on pro-apoptosis signaling as well as anti-apoptosis signaling. Methods In vitro study, after the esophageal cells were exposed to arsenic combined with emodin, the apoptotic rate, release of cytochrome C from mitochondrion, activity of survival-related transcription factor NF-κB and expression of targeted protein survivin were determined. In vivo study, the animal models bearing esophageal tumor cells were administrated with emodin and arsenic intraperitoneally. After chemotherapy, the tumors were weighted and apoptosis of tumor cells, translocation of NF-κB to nuclei and expression of survivin in neoplasms were assayed. Results Emodin enhanced apoptosis of esophageal tumor cells induced by arsenic via augmenting release of cytochrome C from mitochondrion and inhibiting NF-κB activity in ROS dependent manner. Meanwhile, cotreatment of emodin and arsenic enhanced apoptosis of neoplasms, inhibited translocation of NF-κB and down-regulated survivin in neoplams. Conclusion Emodin enhanced apoptosis of esophageal tumor cells in vitro and in vivo. The mechanisms of emodin involved enhancement of pro-apoptotic signaling pathway as well as inhibition of anti-apoptotic signaling pathway. There exists the practical feasibility of emodin in chemotherapy.