两种小分子化合物抗乳腺癌的性质以及机理研究

发布时间：2018-05-26 06:36

本文选题：CuE + HDACi　；参考：《华东师范大学》2015年博士论文

【摘要】：据统计,2013年,美国的女性乳腺癌发生率在所有恶性癌症中排在第一位,致死率排在第二位,仅次于肺癌。尽管随着各种诊断手段以及医疗手段的显著提高,乳腺癌患者的发生率以及死亡率有逐年下降的的趋势。但每年(包括2013)还有超过百万的女性癌症患者死于乳腺癌。乳腺癌原位肿瘤的生长并不是导致患者死亡的主要原因。研究表明,90%以上的乳腺癌患者发生死亡的主要原因是发生了肿瘤转移。尽管在市场上已经有许多治疗乳腺癌的药物,但是治疗乳腺癌的新型药物特别是针对乳腺癌转移的药物研究和开发也是十分必要的。本文的内容主要介绍两种小分子化合物(葫芦素E和组蛋白去乙酰化酶抑制,YF479)抗乳腺癌临床前活性的研究：第一部分：葫芦素E (CuE)通过靶向抑制乳腺癌细胞的迁移和侵袭来抑制乳腺癌的转移。CuE是从葫芦科植物中提取出的一种四环三萜类小分子化合物。已有的研究发现,CuE具有消炎、抗病毒、抗癌症、抗血管新生等功能。但是在抑制乳腺癌转移方面的研究还没有任何报道。在动物实验中,我们发现CuE能显著地抑制乳腺癌转移。体外的迁移和侵袭实验结果表明葫芦素能够显著地抑制乳腺癌细胞的迁移和侵袭。免疫组化(IHC)的实验表明CuE在体内对乳腺癌细胞的增殖和凋亡没有任何作用。这也就说明,CuE抑制乳腺癌的转移主要通过抑制肿瘤细胞的迁移和侵袭。对其抑制转移的机制研究表明,CuE能够阻止微丝的聚合,降低Arp3的表达。同时发现过表达Arp3可以延缓CuE所引起的微丝的解聚。FAK/MMPs信号通路在侵袭和转移中起着关键的作用。我们研究发现CuE能够抑制Src/FAK/Rac1/MMPs信号通路。综合研究结果,我们认为CuE是一个治疗乳腺癌转移的潜在候选药物。第二部分：我们鉴定一种新型的组蛋白去乙酰化酶抑制剂(HDACi)YF479。研究发现YF479能够抑制乳腺癌的生长、转移和复发。传统意义上,肿瘤是一种基因遗传病,而近年来研究表明,表观遗传的改变比如甲基化、乙酰化、泛素化、糖基化等一系列的蛋白质修饰也会引起肿瘤的发生。由于这种表观遗传的改变是一种可逆的过程,这就使得蛋白质修饰的抑制剂用来治疗肿瘤成为可能。组蛋白的乙酰化和去乙酰在正常的细胞中是处于平衡状态的,分别由组蛋白去乙酰化酶(HDAC)以及组蛋白乙酰化转移酶(HAT)调控。研究表明HDAC在乳腺癌异常表达,并可以作为治疗的分子靶点。我们利用酶活试剂盒筛选我们实验室潜在HDACi小分子库,鉴定出一个新型的HDACi, YF479。我们发现YF479能够显著地诱导H3和H4乙酰化。在细胞实验中,我们发现YF479能够诱导细胞的凋亡并引起细胞周期的阻滞。细胞克隆形成实验也显示YF479能显著抑制乳腺癌细胞的克隆形成。体外黏附、迁移和侵袭实验表明YF479能抑制肿瘤细胞的黏附、迁移和侵袭。体内实验也证实YF479能抑制乳腺癌的生长转移和复发,并能够显著提高小鼠的生存率。提示YF479是一个治疗乳腺癌的潜在药物。
[Abstract]:According to statistics, in 2013, the incidence of female breast cancer in the United States was ranked first in all malignant cancers. The mortality rate was second, second only to lung cancer. Although the incidence and mortality rate of breast cancer patients were declining year by year with various diagnostic methods and medical methods, the annual (including 2013) and more than one year was more than one. Millions of female cancer patients die of breast cancer. The growth of breast cancer in situ is not the main cause of death. Studies have shown that more than 90% of breast cancer deaths are mainly due to tumor metastasis. Although many drugs have been used to treat breast cancer in the market, new drugs for the treatment of breast cancer have been found. Especially for breast cancer metastasis research and development of drugs is also very necessary.
The content of this article is mainly about the study of two small molecule compounds (cucurbit E and histone deacetylase inhibition, YF479) on the preclinical activity of breast cancer.
Part one: cucurbit E (CuE) is a small molecular compound of four ring three terpenoids extracted from cucurbit plants by targeting the migration and invasion of mammary cancer cells to inhibit the migration and invasion of breast cancer cells. The existing studies have found that CuE has anti-inflammatory, antiviral, anticancer, antiangiogenic functions, but it inhibits the transformation of breast cancer. In animal experiments, we found that CuE could significantly inhibit the metastasis of breast cancer. In vitro migration and invasion experiments showed that cucurbit could significantly inhibit the migration and invasion of breast cancer cells. Immunohistochemical (IHC) experiments showed that CuE did not proliferate and apoptosis in breast cancer cells in vivo. There is any effect. This suggests that CuE inhibits metastasis of breast cancer mainly by inhibiting migration and invasion of tumor cells. The mechanism of its inhibition of metastasis shows that CuE can prevent the polymerization of microfilament and reduce the expression of Arp3. At the same time, the expression of Arp3 can delay the depolymerization of the microfilaments caused by CuE in the invasion and the invasion of the CuE. Metastasis plays a key role. We have found that CuE can inhibit the Src/FAK/Rac1/MMPs signaling pathway. Combined with the results, we think that CuE is a potential candidate for the treatment of breast cancer metastasis.
The second part: We identified a new type of histone deacetylase inhibitor (HDACi) YF479. study to find that YF479 can inhibit the growth, metastasis and recurrence of breast cancer. In the traditional sense, the tumor is a genetic disease. In recent years, studies have shown that epigenetic alterations such as methylation, acetylation, ubiquitination, glycosylation, etc. Protein modification in the column also causes the occurrence of tumors. Since this epigenetic change is a reversible process, it makes it possible for protein modified inhibitors to treat tumors. Histone acetylation and deacetylation are in a balanced state in normal cells, respectively, by histone deacetylase (HDAC), respectively. And histone acetyltransferase (HAT) regulation. The study shows that HDAC is abnormal expression in breast cancer and can be used as a molecular target for treatment. We use enzyme activity kit to screen the potential HDACi small molecular library in our laboratory and identify a new type of HDACi. YF479. we found that YF479 can significantly induce H3 and H4 acetylation. We found that YF479 can induce cell apoptosis and cause cell cycle arrest. Cell clone formation experiments also showed that YF479 could significantly inhibit the cloning of breast cancer cells. In vitro adhesion, migration and invasion experiments showed that YF479 could inhibit the adhesion, migration and invasion of tumor cells. In vivo experiments also confirmed that YF479 could inhibit breast cancer. The growth, metastasis and relapse can significantly improve the survival rate of mice, suggesting that YF479 is a potential drug for breast cancer.
【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R737.9

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