硫氧还蛋白1抑制剂PX-12抑制肝癌细胞生长并增强其对5-氟尿嘧啶的化疗敏感性

发布时间：2018-06-27 23:25

本文选题：肝细胞癌 + 硫氧还蛋白1　；参考：《华中科技大学》2016年博士论文

【摘要】：目的1-甲基丙2-咪唑二硫(PX-12),是一种硫氧还蛋白1(Thioredoxin 1,Trx1)抑制剂,在多种肿瘤中的作用已经研究证实,但PX-12在肝细胞癌(HCC)中的作用尚未报道。同时PX-12在其他实体肿瘤中仅作为单药研究。本实验的目的是研究PX-12在肝细胞癌中是否能够抑制细胞生长及和5-氟尿嘧啶联用是否具有协同抗肿瘤作用。方法用PX-12和(或)5-氟尿嘧啶处理HepG2和SMMC7721细胞。进行细胞活性实验、平板克隆形成实验、细胞周期检测、活性氧簇(ROS)检测、凋亡检测、蛋白免疫印迹分析、免疫组织化学及动物实验。结果PX-12抑制细胞生长,引起细胞S期阻滞,并且升高了细胞ROS水平。PX-12引起的凋亡增加及抑制集落形成与ROS升高密切相关,抑制ROS产生能够拮抗PX-12引起的凋亡增加及集落形成抑制。PX-12增加了bax的表达、减少了bcl-2的表达,提示PX-12引起的凋亡是线粒体依赖的。体内外实验证实：PX-12和5-氟尿嘧啶联用在抑制肿瘤形成具有协同效应;抑制ROS聚集能够拮抗PX-12和5-氟尿嘧啶的协同效应。结论PX-12具有抗肿瘤的作用,并且和5-氟尿嘧啶联用在治疗肝细胞癌中具有协同作用。PX-12单用或和5-氟尿嘧啶联用可能会应用于临床,用于治疗肝细胞癌或其他肿瘤。
[Abstract]:Objective 1 methyl propyl 2 imidazole disulfide (PX-12) is a thioredoxin 1 Trx1 inhibitor. The role of PX-12 in various tumors has been confirmed, but the role of PX-12 in hepatocellular carcinoma (HCC) has not been reported. At the same time, PX-12 is only used as a single drug in other solid tumors. The aim of this study was to investigate whether PX-12 can inhibit cell growth in hepatocellular carcinoma and whether PX-12 and 5-fluorouracil have synergistic antitumor effects. Methods HepG2 and SMMC7721 cells were treated with PX-12 and / or 5-fluorouracil. Cell activity, plate clone formation, cell cycle, reactive oxygen species (Ros), apoptosis, Western blotting, immunohistochemistry and animal experiments were carried out. Results PX-12 inhibited cell growth, caused cell S phase arrest, and increased Ros level. PX-12 increased apoptosis and inhibited colony formation, which was closely related to the increase of Ros. Inhibition of Ros production could antagonize the increase of apoptosis induced by PX-12 and the inhibition of colony formation. PX-12 increased the expression of bax and decreased the expression of bcl-2, suggesting that the apoptosis induced by PX-12 was mitochondrial dependent. In vitro and in vivo experiments showed that the combination of: PX-12 and 5-fluorouracil had synergistic effect on tumor formation, and inhibition of Ros aggregation could antagonize the synergistic effect of PX-12 and 5-fluorouracil. Conclusion PX-12 has anti-tumor effect and has synergistic effect with 5-fluorouracil in the treatment of hepatocellular carcinoma. PX-12 alone or combined with 5-fluorouracil may be used in clinical treatment of hepatocellular carcinoma or other tumors.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.7

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