發(fā)布時間：2018-01-04 00:12

  本文關(guān)鍵詞：含硒化合物聯(lián)合化療藥物及放射性粒子在抑制腫瘤生長和轉(zhuǎn)移中的研究　出處：《暨南大學(xué)》2016年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 腫瘤 含硒化合物 抗腫瘤 轉(zhuǎn)移 活性氧 分子機(jī)制

【摘要】：現(xiàn)今惡性腫瘤嚴(yán)重威脅著人類身體健康,而化療是治療惡性腫瘤的重要手段。但是近年來,藥物的毒副作用和耐藥現(xiàn)象的出現(xiàn)阻礙了化療在臨床中的應(yīng)用。因此,開發(fā)新型化療藥物及增敏劑,提高腫瘤細(xì)胞對化療藥物的敏感性或?qū)ふ倚碌挠盟幉呗钥滩蝗菥彙６侨梭w生命必需的微量元素之一,具有廣泛的生物學(xué)功能,在人體各個新陳代謝途徑中發(fā)揮著重要作用。近年研究表明,含硒化合物在治療惡性腫瘤中所起的重要作用已經(jīng)被大量的流行病學(xué)、臨床學(xué)研究的結(jié)果所驗證。其中,一些化合物不僅具有良好的抗腫瘤活性,還能夠協(xié)同多種臨床化療藥物以提高其對腫瘤的敏感性從而減少耐藥現(xiàn)象的出現(xiàn)。所以基于硒化合物高效低毒且生物利用度高的特點(diǎn),含硒化合物藥物的開發(fā)已成為一個熱點(diǎn)。本論文首先探討了七個有機(jī)硒化合物即新聯(lián)苯并硒二唑?qū)Π螂装┘?xì)胞的抗腫瘤效果及作用機(jī)理,并檢測了具有代表性的化合物對癌細(xì)胞的轉(zhuǎn)移的抑制效果。同時,根據(jù)有機(jī)硒獨(dú)特的協(xié)同增敏的特點(diǎn),將硒化合物與金屬離子結(jié)合形成含硒金屬配合物(FeSe),我們不僅檢測了它的體外、體內(nèi)抗腫瘤活性,而且通過對構(gòu)效關(guān)系的分析闡述了其協(xié)同增敏化療藥物(TRAIL)的效果及對其抗腫瘤分子機(jī)制進(jìn)行了分析,最后,我們研究了具有較低毒副作用的納米硒GP-SeNPs聯(lián)合放射性粒子~(125)I的體外抗腫瘤活性及作用機(jī)理。具體研究結(jié)果如下:1.本章對新聯(lián)苯并硒二唑衍生物抑制膀胱癌細(xì)胞的生長、轉(zhuǎn)移及其抗腫瘤機(jī)制的研究,結(jié)果表明:新聯(lián)苯并硒二唑衍生物具有良好的抗腫瘤活性,其選擇性及穩(wěn)定性都較好,對膀胱癌細(xì)胞的轉(zhuǎn)移也有顯著的抑制作用。進(jìn)一步機(jī)制研究發(fā)現(xiàn)該化合物能夠通過胞吞以及溶酶體的形成進(jìn)入腫瘤細(xì)胞,引起活性氧ROS在胞內(nèi)的累積,活化了caspase繼而引起激酶AKT,ERK和JNK的表達(dá)水平的改變,即抑制AKT,ERK的磷酸化并活化JNK,p53,同時也激活MAPKs,最終誘導(dǎo)了癌細(xì)胞的凋亡。2.本章研究了含硒鐵配合物(FeSe)在細(xì)胞和動物水平的抗腫瘤活性,及其與化療藥物TRAIL聯(lián)合使用作為化療增敏劑的效果,并通過對構(gòu)效關(guān)系的分析和抗腫瘤分子機(jī)制的闡述揭示引入含硒配體對金屬配合物的抗腫瘤活性的影響。結(jié)果顯示:含硒鐵配合物FeSe不僅能更好的抑制腫瘤細(xì)胞,還能更好的抑制腫瘤多細(xì)胞球(MCTSs)的大小及具有較好的穿透腫瘤球能力,除此之外還可以更好的抑制腫瘤細(xì)胞HeLa的轉(zhuǎn)移;能更好的協(xié)同增加TRAIL誘導(dǎo)腫瘤細(xì)胞的凋亡。而機(jī)制研究表明聯(lián)合處理通過介導(dǎo)ROS在胞內(nèi)的積累而激活了caspase,從而調(diào)節(jié)MAPKs,AKT的表達(dá),以及DNA損傷介導(dǎo)的p53磷酸化,進(jìn)而調(diào)控Bcl-2家族蛋白表達(dá)量的變化,死亡受體通路相關(guān)蛋白表達(dá)含量也發(fā)生改變,最終增強(qiáng)TRAIL誘導(dǎo)的細(xì)胞凋亡。此外利用MR進(jìn)行體內(nèi)初步研究表明含硒鐵配合物FeSe能降低實體瘤的活性。3.本章探究了功能化的納米硒GP-SeNPs s與放射性粒子~(125)I共作用體外抗腫瘤的活性。結(jié)果表明功能化的納米硒GP-SeNPs聯(lián)合放射性粒子~(125)I通過誘導(dǎo)細(xì)胞凋亡和G2/M期阻滯的方式抑制HeLa細(xì)胞的生長。而進(jìn)一步分子機(jī)制研究表明功能化的納米硒GP-SeNPs聯(lián)合放射性粒子~(125)I通過介導(dǎo)細(xì)胞內(nèi)活性氧的累積引起caspase家族蛋白的活化從而引起的DNA的損傷誘導(dǎo)細(xì)胞凋亡。綜上所述,本論文綜合運(yùn)用多種生物學(xué)方法對不同形態(tài)的硒的抗腫瘤活性研究,利用用藥新策略提高其抗腫瘤效果并深入闡述了其作用機(jī)制。而研究結(jié)果預(yù)示了含硒化合物在化療中的潛在應(yīng)用價值。該文不僅拓寬了新型藥物的設(shè)計思路,還探討出用藥新策略,該研究為含硒化合物更深一步走進(jìn)臨床治療領(lǐng)域提供了科學(xué)依據(jù)。
[Abstract]:The malignant tumor is a serious threat to human health, and chemotherapy is an important means for the treatment of malignant tumors. But in recent years, the emergence of drug side effects and drug resistance phenomenon of drug application has hindered the chemotherapy in clinic. Therefore, the development of new chemotherapeutic agents and sensitizing agents, enhance the sensitivity of tumor cells to chemotherapy drugs or find the new treatment strategies is urgently needed. And selenium is one of the necessary trace element for human life has extensive biological functions, and plays an important role in the human body each way. The new supersedes the old. recent studies indicate that selenium compounds have an important role in the treatment of malignant tumor has been a large number of epidemiological, clinical validation studies results. Among them, some compounds have good anti-tumor activity, but also a variety of clinical cooperative chemotherapy drugs to increase the sensitivity of tumor decreased from There is less resistance phenomenon. So the selenium compounds with high efficiency and low toxicity and high bioavailability of selenium compounds based on the development of drugs has become a hot spot. This paper discusses the antitumor effect and mechanism of seven organic selenium compounds namely new biphenyl and selenium two Triazole on bladder cancer cells, and detected the inhibitory effect of transfer compound representative of cancer cells. At the same time, according to the characteristics of collaborative sensitization of organic selenium will form a unique, selenium containing metal complexes with selenium compounds and metal ions (FeSe), we examined its in vitro antitumor activity in vivo, and through the analysis of structure-activity relationship discusses the synergistic sensitizing effect of chemotherapeutic drugs (TRAIL) and its antitumor molecular mechanism are analyzed. Finally, we studied with nano selenium GP-SeNPs combined with radioactive particles with low toxic and side effects of ~ (125 ) I anti-tumor activity in vitro and the mechanism. The main results are as follows: 1. this chapter on the growth of new biphenyl and se two derivatives inhibit bladder cancer cells, and its anti tumor mechanism research, the results show that the new transfer of biphenyl and se two pyrazole derivatives have good anti-tumor activity, selectivity and stability well, the transfer of bladder cancer cells was significantly inhibited. Further study found that the compound mechanism through endocytosis and lysosomal formation into tumor cells, accumulation of ROS in ROS induced intracellular caspase activation, followed by kinase AKT, the expression level of ERK and JNK change, namely the inhibition of AKT, the phosphorylation of ERK and activation of JNK, p53, and MAPKs activation, eventually induces apoptosis of cancer cell.2. were studied in this chapter containing selenium and iron complexes (FeSe) on the anti-tumor activity of cell and animal level, and chemotherapy TRAIL combined with chemotherapy drugs as the sensitizer effect, and through the analysis of structure-activity relationship and molecular mechanism of antitumor activity reveal influence into selenium containing ligands on the antitumor activity of metal complexes. The results showed that selenium containing iron complex FeSe inhibition of tumor cell can better inhibit tumor spheroids. Better (MCTSs) and the size of tumor sphere has good penetration ability, inhibit tumor metastasis of HeLa cells in addition to better; better apoptosis synergistically increased TRAIL induced by tumor cells. And the study of Ming combined treatment table mechanism mediated by ROS in intracellular accumulation and activation of caspase. To regulate the expression of AKT, MAPKs, and DNA damage mediated phosphorylation of p53, thereby regulating the expression of Bcl-2 family proteins, occurrence of the death receptor pathway related protein content change, and ultimately enhance T Cell apoptosis induced by RAIL. In addition to the use of MR in vivo preliminary studies showed that.3. activity of selenium containing iron complexes FeSe can reduce the solid tumors, this chapter explores the function of S and GP-SeNPs nano se ~ (125) I in vitro antitumor activity. The results show that the nano selenium functionalized GP-SeNPs combined with radioactive particle the ~ (125) I inhibition of HeLa cells by inducing apoptosis and G2/M arrest. The growth and molecular mechanism of nano selenium further showed that GP-SeNPs combined with radioactive particles functionalized by ~ (125) I mediated accumulation of intracellular ROS induced activation of caspase family proteins which caused by DNA induced injury cell apoptosis. In summary, the antitumor activity of the integrated use of a variety of biological methods of different forms of selenium, a new strategy to improve the anti tumor effect of drug use and are expounded in this paper. The mechanism of action. And the results of the study indicate the potential application of selenium compounds in chemotherapy. This paper not only broaden the design ideas for new drugs, but also to explore the new strategy of drug use, this study provides a scientific basis for deeper selenium compounds, step into the field of clinical treatment.

【學(xué)位授予單位】：暨南大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R730.5

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