米诺环素联合顺铂通过诱导S期阻滞和凋亡协同抑制肝癌增殖的研究
发布时间：2019-02-11 11:01
【摘要】：目的：半合成四环素,米诺环素,是一种浸润的组织和血液高度亲脂性的药物。已有研究显示米诺环素在抗炎以及神经系统保护方面的功能和机制。然而米诺环素在肝细胞癌(HCC)中的抗肿瘤作用还未有研究报道。 方法：采用体内实验、流式细胞术和蛋白免疫印迹法等实验研究米诺环素在HCC细胞中的功能。我们对L02、HepG2和Huh7细胞应用米诺环素和联合应用顺铂,并对细胞的生长特性进行了研究。应用细胞周期和细胞凋亡的分析来探讨米诺环素在肝细胞癌中调控肿瘤增殖的机制。 结果：米诺环素引起S期细胞周期阻滞,并诱导细胞凋亡,p27、cleaved-caspase8、cleaved-PARP-1和cleaved-caspase表达相应上调。米诺环素发挥抑制肝细胞癌增殖的作用主要与PARP-1相关。低剂量顺铂和米诺环素的联合应用使得细胞S期阻滞和凋亡率增加,协同抑制肝细胞癌增殖。体内实验证实米诺环素联合应用顺铂对裸鼠皮下成瘤发挥抑制作用。 结论：米诺环素引起S期细胞周期阻滞,诱导细胞凋亡抑制肝细胞癌的增殖,其机制可能通过增加米诺环素对PARP-1的抑制效应来实现的。低剂量顺铂联合应用米诺环素,引起S期阻滞和细胞凋亡率增加,发挥协同抑制肝细胞癌增殖的作用。
[Abstract]:Objective: semi-synthetic tetracycline, minocycline, is an infiltrating tissue and blood high-lipophilic drug. Studies have shown the role and mechanism of minocycline in anti-inflammatory and neuroprotective effects. However, the anti-tumor effect of minocycline in hepatocellular carcinoma (HCC) has not been reported. Methods: the function of minocycline in HCC cells was studied by flow cytometry and Western blotting in vivo. We applied minocycline and cisplatin to L02 HepG2 and Huh7 cells, and studied the growth characteristics of L02 HepG2 and Huh7 cells. Cell cycle and apoptosis were analyzed to explore the mechanism of minocycline in regulating tumor proliferation in hepatocellular carcinoma. Results: minocycline induced cell cycle arrest and apoptosis in S phase. The expression of p27 cleaved-caspase8 cleaved-PARP-1 and cleaved-caspase was up-regulated. The inhibitory effect of minocycline on the proliferation of hepatocellular carcinoma is mainly related to PARP-1. The combination of low dose cisplatin and minocycline increased cell S phase arrest and apoptosis rate, and synergistically inhibited the proliferation of hepatocellular carcinoma. In vivo experiments confirmed the inhibitory effect of minocycline combined with cisplatin on subcutaneous tumorigenesis in nude mice. Conclusion: minocycline induces S phase cell cycle arrest and induces apoptosis to inhibit the proliferation of hepatocellular carcinoma. The mechanism may be achieved by increasing the inhibitory effect of minocycline on PARP-1. Low dose cisplatin combined with minocycline could induce S-phase arrest and increase apoptosis rate, and play a synergistic role in inhibiting the proliferation of hepatocellular carcinoma.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.7
[Abstract]:Objective: semi-synthetic tetracycline, minocycline, is an infiltrating tissue and blood high-lipophilic drug. Studies have shown the role and mechanism of minocycline in anti-inflammatory and neuroprotective effects. However, the anti-tumor effect of minocycline in hepatocellular carcinoma (HCC) has not been reported. Methods: the function of minocycline in HCC cells was studied by flow cytometry and Western blotting in vivo. We applied minocycline and cisplatin to L02 HepG2 and Huh7 cells, and studied the growth characteristics of L02 HepG2 and Huh7 cells. Cell cycle and apoptosis were analyzed to explore the mechanism of minocycline in regulating tumor proliferation in hepatocellular carcinoma. Results: minocycline induced cell cycle arrest and apoptosis in S phase. The expression of p27 cleaved-caspase8 cleaved-PARP-1 and cleaved-caspase was up-regulated. The inhibitory effect of minocycline on the proliferation of hepatocellular carcinoma is mainly related to PARP-1. The combination of low dose cisplatin and minocycline increased cell S phase arrest and apoptosis rate, and synergistically inhibited the proliferation of hepatocellular carcinoma. In vivo experiments confirmed the inhibitory effect of minocycline combined with cisplatin on subcutaneous tumorigenesis in nude mice. Conclusion: minocycline induces S phase cell cycle arrest and induces apoptosis to inhibit the proliferation of hepatocellular carcinoma. The mechanism may be achieved by increasing the inhibitory effect of minocycline on PARP-1. Low dose cisplatin combined with minocycline could induce S-phase arrest and increase apoptosis rate, and play a synergistic role in inhibiting the proliferation of hepatocellular carcinoma.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.7
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