【摘要】：目的：半合成四環(huán)素,米諾環(huán)素,是一種浸潤的組織和血液高度親脂性的藥物。已有研究顯示米諾環(huán)素在抗炎以及神經(jīng)系統(tǒng)保護(hù)方面的功能和機(jī)制。然而米諾環(huán)素在肝細(xì)胞癌(HCC)中的抗腫瘤作用還未有研究報道。 方法：采用體內(nèi)實(shí)驗(yàn)、流式細(xì)胞術(shù)和蛋白免疫印跡法等實(shí)驗(yàn)研究米諾環(huán)素在HCC細(xì)胞中的功能。我們對L02、HepG2和Huh7細(xì)胞應(yīng)用米諾環(huán)素和聯(lián)合應(yīng)用順鉑,并對細(xì)胞的生長特性進(jìn)行了研究。應(yīng)用細(xì)胞周期和細(xì)胞凋亡的分析來探討米諾環(huán)素在肝細(xì)胞癌中調(diào)控腫瘤增殖的機(jī)制。 結(jié)果：米諾環(huán)素引起S期細(xì)胞周期阻滯,并誘導(dǎo)細(xì)胞凋亡,p27、cleaved-caspase8、cleaved-PARP-1和cleaved-caspase表達(dá)相應(yīng)上調(diào)。米諾環(huán)素發(fā)揮抑制肝細(xì)胞癌增殖的作用主要與PARP-1相關(guān)。低劑量順鉑和米諾環(huán)素的聯(lián)合應(yīng)用使得細(xì)胞S期阻滯和凋亡率增加,協(xié)同抑制肝細(xì)胞癌增殖。體內(nèi)實(shí)驗(yàn)證實(shí)米諾環(huán)素聯(lián)合應(yīng)用順鉑對裸鼠皮下成瘤發(fā)揮抑制作用。 結(jié)論：米諾環(huán)素引起S期細(xì)胞周期阻滯,誘導(dǎo)細(xì)胞凋亡抑制肝細(xì)胞癌的增殖,其機(jī)制可能通過增加米諾環(huán)素對PARP-1的抑制效應(yīng)來實(shí)現(xiàn)的。低劑量順鉑聯(lián)合應(yīng)用米諾環(huán)素,引起S期阻滯和細(xì)胞凋亡率增加,發(fā)揮協(xié)同抑制肝細(xì)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.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R735.7

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