含硒化合物联合化疗药物及放射性粒子在抑制肿瘤生长和转移中的研究

发布时间：2018-01-04 00:12

本文关键词：含硒化合物联合化疗药物及放射性粒子在抑制肿瘤生长和转移中的研究　出处：《暨南大学》2016年硕士论文　论文类型：学位论文

【摘要】：现今恶性肿瘤严重威胁着人类身体健康,而化疗是治疗恶性肿瘤的重要手段。但是近年来,药物的毒副作用和耐药现象的出现阻碍了化疗在临床中的应用。因此,开发新型化疗药物及增敏剂,提高肿瘤细胞对化疗药物的敏感性或寻找新的用药策略刻不容缓。而硒是人体生命必需的微量元素之一,具有广泛的生物学功能,在人体各个新陈代谢途径中发挥着重要作用。近年研究表明,含硒化合物在治疗恶性肿瘤中所起的重要作用已经被大量的流行病学、临床学研究的结果所验证。其中,一些化合物不仅具有良好的抗肿瘤活性,还能够协同多种临床化疗药物以提高其对肿瘤的敏感性从而减少耐药现象的出现。所以基于硒化合物高效低毒且生物利用度高的特点,含硒化合物药物的开发已成为一个热点。本论文首先探讨了七个有机硒化合物即新联苯并硒二唑对膀胱癌细胞的抗肿瘤效果及作用机理,并检测了具有代表性的化合物对癌细胞的转移的抑制效果。同时,根据有机硒独特的协同增敏的特点,将硒化合物与金属离子结合形成含硒金属配合物(FeSe),我们不仅检测了它的体外、体内抗肿瘤活性,而且通过对构效关系的分析阐述了其协同增敏化疗药物(TRAIL)的效果及对其抗肿瘤分子机制进行了分析,最后,我们研究了具有较低毒副作用的纳米硒GP-SeNPs联合放射性粒子~(125)I的体外抗肿瘤活性及作用机理。具体研究结果如下:1.本章对新联苯并硒二唑衍生物抑制膀胱癌细胞的生长、转移及其抗肿瘤机制的研究,结果表明:新联苯并硒二唑衍生物具有良好的抗肿瘤活性,其选择性及稳定性都较好,对膀胱癌细胞的转移也有显著的抑制作用。进一步机制研究发现该化合物能够通过胞吞以及溶酶体的形成进入肿瘤细胞,引起活性氧ROS在胞内的累积,活化了caspase继而引起激酶AKT,ERK和JNK的表达水平的改变,即抑制AKT,ERK的磷酸化并活化JNK,p53,同时也激活MAPKs,最终诱导了癌细胞的凋亡。2.本章研究了含硒铁配合物(FeSe)在细胞和动物水平的抗肿瘤活性,及其与化疗药物TRAIL联合使用作为化疗增敏剂的效果,并通过对构效关系的分析和抗肿瘤分子机制的阐述揭示引入含硒配体对金属配合物的抗肿瘤活性的影响。结果显示:含硒铁配合物FeSe不仅能更好的抑制肿瘤细胞,还能更好的抑制肿瘤多细胞球(MCTSs)的大小及具有较好的穿透肿瘤球能力,除此之外还可以更好的抑制肿瘤细胞HeLa的转移;能更好的协同增加TRAIL诱导肿瘤细胞的凋亡。而机制研究表明联合处理通过介导ROS在胞内的积累而激活了caspase,从而调节MAPKs,AKT的表达,以及DNA损伤介导的p53磷酸化,进而调控Bcl-2家族蛋白表达量的变化,死亡受体通路相关蛋白表达含量也发生改变,最终增强TRAIL诱导的细胞凋亡。此外利用MR进行体内初步研究表明含硒铁配合物FeSe能降低实体瘤的活性。3.本章探究了功能化的纳米硒GP-SeNPs s与放射性粒子~(125)I共作用体外抗肿瘤的活性。结果表明功能化的纳米硒GP-SeNPs联合放射性粒子~(125)I通过诱导细胞凋亡和G2/M期阻滞的方式抑制HeLa细胞的生长。而进一步分子机制研究表明功能化的纳米硒GP-SeNPs联合放射性粒子~(125)I通过介导细胞内活性氧的累积引起caspase家族蛋白的活化从而引起的DNA的损伤诱导细胞凋亡。综上所述,本论文综合运用多种生物学方法对不同形态的硒的抗肿瘤活性研究,利用用药新策略提高其抗肿瘤效果并深入阐述了其作用机制。而研究结果预示了含硒化合物在化疗中的潜在应用价值。该文不仅拓宽了新型药物的设计思路,还探讨出用药新策略,该研究为含硒化合物更深一步走进临床治疗领域提供了科学依据。
[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.

【学位授予单位】：暨南大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R730.5

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