本文選題：去甲斑蝥素 + 絨癌　； 參考：《重慶醫(yī)科大學(xué)》2017年博士論文

【摘要】：去甲斑蝥素(Norcantharidin,NCTD)是通過(guò)去除斑蝥素分子中2,3-甲基所得的化合物,是我國(guó)首先人工合成并擁有獨(dú)立知識(shí)產(chǎn)權(quán)的新型治癌藥物。與斑蝥素相比,它具有更低的毒性,且具有獨(dú)特的升白細(xì)胞作用。已有的研究表明,去甲斑蝥素可以保護(hù)正常肝細(xì)胞免受因脂多糖(LPS)導(dǎo)致的損傷;減弱腎小管間質(zhì)纖維化,保護(hù)腎臟;還對(duì)人身體免疫系統(tǒng)具有良好的調(diào)節(jié)作用。除了以上的特點(diǎn)之外,去甲斑蝥素還具有較強(qiáng)的抗癌活性,它對(duì)多種腫瘤具有良好的治療效果。這些腫瘤包括卵巢癌、前列腺癌、宮頸癌、肝癌等。利用抗癌藥提升腫瘤細(xì)胞內(nèi)的活性氧水平從而誘導(dǎo)細(xì)胞凋亡被認(rèn)為是一條潛在的抗癌途徑�；钚匝醯纳呖梢哉T導(dǎo)細(xì)胞凋亡與自噬,使細(xì)胞死亡。關(guān)于NCTD對(duì)人絨癌及皮膚癌方面的研究仍然知之甚少。我們?cè)谇捌趯?shí)驗(yàn)研究中發(fā)現(xiàn),NCTD可誘導(dǎo)人絨癌JEG-3細(xì)胞與人皮膚鱗狀細(xì)胞癌A431細(xì)胞活性氧明顯升高,至于它能否誘導(dǎo)這兩種癌細(xì)胞凋亡及自噬等情況,值得進(jìn)一步研究。第一部分:NCTD對(duì)人絨癌JEG-3細(xì)胞的增殖、凋亡和自噬的影響,以及與5-FU化療增敏作用目的:探討NCTD對(duì)人絨癌JEG-3細(xì)胞的增殖能力、凋亡和自噬的影響及分子機(jī)制。此外,NCTD對(duì)絨癌主要化療藥5-FU是否具有增敏作用。方法:mtt實(shí)驗(yàn)檢測(cè)細(xì)胞增殖的變化,流式細(xì)胞術(shù)檢測(cè)細(xì)胞增殖周期,annexinv-fitc熒光雙染法檢測(cè)細(xì)胞凋亡,dapi染色法和hochest33258染色法檢測(cè)凋亡細(xì)胞形態(tài),電鏡觀察細(xì)胞凋亡與自噬。我們還使用相關(guān)試劑盒檢測(cè)凋亡、活性氧水平、膜電位、自噬陽(yáng)性細(xì)胞、mda及caspase-3,-9酶活性變化,最后用定量pcr方法檢測(cè)抗氧化基因的mrna表達(dá),western-blot法檢測(cè)p21、cyclinb1、fas、fasl、bcl-2、bax、mtor、p62、beclin1、lc3-Ⅱ蛋白的表達(dá)。結(jié)果:1.nctd對(duì)人絨癌jeg-3細(xì)胞生長(zhǎng)增殖有明顯的抑制作用;nctd能引起jeg-3細(xì)胞g2期阻滯,其分子機(jī)制可能是通過(guò)增加p21蛋白表達(dá)和下調(diào)cyclinb1蛋白而引起的。2.nctd能提升jeg-3細(xì)胞中ros水平,同時(shí)細(xì)胞內(nèi)總的sod酶活性降低,mda含量升高。定量pcr結(jié)果提示,抗氧化酶sod1、prdx1、prdx2、prdx3以及細(xì)胞因子il-6mrna表達(dá)隨著nctd濃度的增加而降低,提示了nctd作用jeg-3細(xì)胞,誘導(dǎo)ros水平有可能是通過(guò)下調(diào)抗氧化物相關(guān)基因表達(dá)進(jìn)行的。3通過(guò)hochest33258和dapi染色、電鏡觀察細(xì)胞形態(tài)及流式細(xì)胞術(shù)檢測(cè)凋亡率及膜電位,結(jié)果提示了nctd明顯誘導(dǎo)jeg-3細(xì)胞凋亡,同時(shí)細(xì)胞中bcl-2蛋白表達(dá)降低,而bax、fas、fasl蛋白表達(dá)增加4.為了探索活性氧水平升高是nctd誘導(dǎo)jeg-3細(xì)胞凋亡的主要原因,我們采用活性氧清除劑n-乙酰半胱氨酸(nac)與nctd共同作用進(jìn)行反向求證。結(jié)果發(fā)現(xiàn)nac可逆轉(zhuǎn)nctd誘導(dǎo)jeg-3細(xì)胞凋亡,其機(jī)制與nac能降低caspase-3、9酶活性有關(guān)。5.與單獨(dú)使用nctd或5-fu比較,nctd與5fu聯(lián)合使用,對(duì)jeg-3細(xì)胞具有更明顯的抑制效果,其機(jī)制與增加caspase-3、9酶活性相關(guān)。6.nctd對(duì)jeg-3細(xì)胞自噬影響的實(shí)驗(yàn)中,我們發(fā)現(xiàn),nctd能誘導(dǎo)jeg-3細(xì)胞自噬,其機(jī)制與mtor、akt、p62、lc3-Ⅱ及beclin1蛋白表達(dá)變化相關(guān)。為了進(jìn)一步論證自噬與活性氧的關(guān)系,我們用nac與nctd共同處理細(xì)胞,發(fā)現(xiàn)nac可以明顯減輕nctd誘導(dǎo)的自噬,同時(shí)使自噬相關(guān)蛋白beclin1、p62表達(dá)改變,結(jié)果提示了ros升高是nctd誘導(dǎo)jeg-3細(xì)胞自噬的主要原因。結(jié)論:nctd主要通過(guò)提高jeg-3細(xì)胞活性氧水平,誘導(dǎo)細(xì)胞凋亡、自噬,其機(jī)制可能與nctd能改變jeg-3細(xì)胞內(nèi)的p21、cyclinb1、fas、fasl、bcl-2、bax、mtor、p62、beclin1、lc3-Ⅱ蛋白表達(dá)有關(guān)。另外,nctd可以抑制jeg-3細(xì)胞增殖,使細(xì)胞周期阻滯在g2期,可以對(duì)5-fu治療絨癌具有增敏作用。本實(shí)驗(yàn)為nctd治療人絨癌提供了重要的實(shí)驗(yàn)依據(jù),進(jìn)一步拓展了nctd作為抗癌藥的應(yīng)用領(lǐng)域。第二部分:nctd對(duì)人皮膚鱗狀細(xì)胞癌a431細(xì)胞的增殖、凋亡及轉(zhuǎn)移的影響,目的:探討nctd對(duì)人皮膚鱗狀細(xì)胞癌a431細(xì)胞的增殖能力、凋亡和侵襲轉(zhuǎn)移的影響及分子機(jī)制。方法:mtt實(shí)驗(yàn)檢測(cè)細(xì)胞增殖的變化,流式細(xì)胞術(shù)觀察細(xì)胞周期變化,annexinv-fitc熒光雙染法檢測(cè)細(xì)胞凋亡,以及使用dapi染色法檢測(cè)凋亡細(xì)胞形態(tài)。我們還使用相關(guān)試劑盒檢測(cè)細(xì)胞活性氧水平、膜電位、sod、mda及caspase-3,-9酶活性變化。另外,我們使用小室實(shí)驗(yàn)檢測(cè)細(xì)胞侵襲轉(zhuǎn)移能力,用劃痕修復(fù)法檢測(cè)細(xì)胞的遷移能力,western-blot法檢測(cè)p21、cyclinb1、fas、fasl、bcl-2、bax、vegf、mmp-2、mmp-9等蛋白表達(dá)。結(jié)果:1.nctd對(duì)a431細(xì)胞生長(zhǎng)增殖有明顯的抑制作用,引起a431細(xì)胞g2期阻滯。其分子機(jī)制可能是通過(guò)增加p21蛋白表達(dá)和下調(diào)cyclinb1蛋白而引起的。2.nctd能升高ros水平,誘導(dǎo)a431細(xì)胞凋亡率增加,同時(shí)細(xì)胞中bcl-2蛋白表達(dá)降低,而bax、fas、fasl蛋白表達(dá)增加。3.為了探索是否由于活性氧水平升高誘導(dǎo)a431細(xì)胞凋亡,我們采用活性氧清除劑n-乙酰半胱氨酸(nac)與nctd共同作用。發(fā)現(xiàn)nac可減少nctd誘導(dǎo)的凋亡,其機(jī)制與nac能降低caspase-3,9酶活性有關(guān)。提示nctd通過(guò)增加ros水平,誘導(dǎo)a431細(xì)胞凋亡。5.transwel小室、劃痕修復(fù)、黏附及western-blot等實(shí)驗(yàn)發(fā)現(xiàn),nctd對(duì)a431細(xì)胞的侵襲遷移和黏附能力均有明顯的抑制,其機(jī)制可能是與nctd降低細(xì)胞內(nèi)的vegf及mmp-2,-9蛋白表達(dá)水平有關(guān)。結(jié)論:nctd可明顯抑制a431細(xì)胞的增殖和轉(zhuǎn)移能力,并且可以通過(guò)活性氧途徑誘導(dǎo)細(xì)胞凋亡。這些研究結(jié)果為nctd治療皮膚癌提供了重要的實(shí)驗(yàn)依據(jù),進(jìn)一步擴(kuò)大了nctd作為抗癌藥的應(yīng)用領(lǐng)域。
[Abstract]:Norcantharidin (Norcantharidin, NCTD) is the compound removal of cantharidin molecule 2,3- methyl income, is a new type of drugs in our country first synthetic and independent intellectual property rights. Compared with cantharidin, which has lower toxicity, and has leukogenic unique role. Previous studies show that to norcantharidin can protect cells from normal liver by lipopolysaccharide (LPS) induced injury; reduced renal interstitial fibrosis, protect the kidney; also has the good effect on human body immune system. In addition to the above features, norcantharidin has strong anticancer activity, it has a good curative effect on a variety of tumors. These tumors including ovarian cancer, prostate cancer, cervical cancer, liver cancer and so on. The use of anticancer drugs enhance the ROS level in tumor cells to induce apoptosis is considered to be a potential anti-cancer Way. Increased ROS can induce cell apoptosis and autophagy, cause cell death. Research on human choriocarcinoma and skin cancer NCTD remains poorly understood. We found in the initial experiments, NCTD induced human choriocarcinoma JEG-3 cells and the activity of human skin squamous cell carcinoma A431 cell oxygen increased significantly, as it can in these two kinds of cancer cell apoptosis and autophagy, is worthy of further study. The first part: NCTD on the proliferation of human choriocarcinoma JEG-3 cells, apoptosis and autophagy, and the sensitivity of objective and 5-FU increased chemotherapy: To investigate the proliferation ability of NCTD on human choriocarcinoma JEG-3 cells, apoptosis and autophagy and its molecular mechanism in addition. Whether or not, NCTD has sensitizing effect on choriocarcinoma main chemotherapy drug 5-FU. Methods: the changes of cell proliferation by MTT assay, the cell cycle was detected by flow cytometry, annexinv-fitc double fluorescent staining method to detect cell Apoptosis, DAPI staining and Hochest33258 staining method to detect cell apoptosis, apoptosis and autophagy were observed. We also use the related kit for detection of apoptosis, ROS level, membrane potential, autophagy positive cells, MDA and Caspase-3, the changes of -9 activity, expression finally quantitative PCR method for detection of antioxidant genes mRNA, detection p21, Western-blot cyclinB1, Fas, FasL, Bcl-2, Bax, mTOR, p62, Beclin1, expression of lc3- protein. Results: the proliferation of 1.nctd significantly inhibited the growth of human choriocarcinoma JEG-3 cells; NCTD can cause JEG-3 cell arrest in G2 phase and its molecular mechanism may be through increasing p21 protein expression and down-regulation of cyclinB1 protein caused by.2.nctd can improve the level of ROS in JEG-3 cells, and SOD enzyme activity in total cell decreased, MDA content increased. The quantitative PCR results suggest that antioxidant enzymes SOD1, Prdx1, prdx2, prdx3 and il-6mrn cytokines The expression of a decreased with the increase of NCTD concentration, suggesting that JEG-3 cells induced by NCTD, ROS levels may be.3 by Hochest33258 and DAPI staining by down regulating the expression of antioxidant related gene expression, electron microscope and detect the apoptosis rate and membrane potential of flow cytometry, the results revealed that NCTD significantly induced apoptosis in JEG-3 cells at the same time, the expression of Bcl-2 protein in the cells decreased, while Bax, Fas, FasL protein expression increased 4. to explore increased levels of reactive oxygen species is a major cause of NCTD induced apoptosis in JEG-3 cells, we use the active oxygen scavenger of n- acetylcysteine (NAC) reverse proof and NCTD together. The results showed that NAC could reverse NCTD induced apoptosis in JEG-3 cells the mechanism, and NAC can reduce the activity of caspase-3,9.5. and the use of NCTD or 5-FU alone, the combined use of NCTD and 5FU, has more obvious inhibition on JEG-3 cells The effect, mechanism and increase caspase-3,9 activity of.6.nctd in autophagy of JEG-3 cells in the experiment, we found that NCTD could induce autophagy in JEG-3 cells, and the mechanism of mTOR, Akt, p62, lc3- II and Beclin1 protein expression changes. In order to further demonstrate the relationship between autophagy and active oxygen, we use NAC and NCTD CO treatment of cells, found that NAC can alleviate NCTD induced autophagy, and autophagy related protein Beclin1, expression of p62, the results suggest that the increase in ROS is the main reason of NCTD induced autophagy in JEG-3 cells. Conclusion: NCTD mainly through JEG-3 cells increased levels of reactive oxygen species, apoptosis, autophagy, and its mechanism may be NCTD can change the JEG-3 cells in p21, cyclinB1, Fas, FasL, Bcl-2, Bax, mTOR, p62, Beclin1, lc3- II protein expression. In addition, NCTD can inhibit the proliferation of JEG-3 cells, induce cell cycle arrest in G2 phase, can be 5 -fu treatment of choriocarcinoma have a sensitizing effect. It provides an important experimental basis for the experimental treatment of human choriocarcinoma NCTD, to further expand the application field of NCTD as anticancer drugs. The second part: NCTD on the proliferation of human skin squamous cell carcinoma A431 cells, influence, apoptosis and metastasis Objective: To investigate the proliferation ability of NCTD in squamous cell carcinoma human skin A431 cells, apoptosis and metastasis and molecular mechanisms. Methods: the changes of cell proliferation by MTT assay, flow cytometry cell cycle, annexinv-fitc fluorescence method to detect cell apoptosis, and to use DAPI staining method to detect the morphology of apoptotic cells. We also use the kit ROS the level of detection of membrane potential, SOD, MDA and Caspase-3, the changes of -9 activity. In addition, we use assay cell invasion and metastasis, cell migration by scratch repair method, The detection of p21, Western-blot cyclinB1, Fas, FasL, Bcl-2, Bax, VEGF, MMP-2, expression of MMP-9 protein. Results: the proliferation of 1.nctd significantly inhibited the growth of A431 cells, A431 induced G2 cell cycle arrest. Its molecular mechanism may be through increasing the expression of p21 protein and cyclinB1 protein caused by.2.nctd modulation to increase the level of ROS, induced A431 cell apoptosis rate increased, while the cells in the lower expression of Bcl-2, Bax, Fas, FasL increased the expression of.3. in order to explore whether due to elevated levels of reactive oxygen species induced apoptosis in A431 cells, we use the active oxygen scavenger of n- acetylcysteine (NAC) together with NCTD. It is found that NAC can decrease apoptosis induced by NCTD, and the mechanism of NAC on activity of caspase-3,9. NCTD by increasing the level of ROS, A431 cell apoptosis induced by.5.transwel cell adhesion, scratch repair, discovery and Western-blot experiment, NCTD has inhibited the invasion of A431 cells migration and adhesion obviously, its mechanism may be related with the decrease of VEGF and NCTD in MMP-2 cells, the expression level of -9 protein. Conclusion: NCTD can inhibit the proliferation and metastasis of A431 cells, and can induce cell apoptosis through ROS pathway. These results provide an important experimental basis for NCTD treatment of skin cancer, to further expand the application field of NCTD as anticancer drugs.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R96

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