本文選題：CuE + HDACi　； 參考：《華東師范大學(xué)》2015年博士論文

【摘要】：據(jù)統(tǒng)計,2013年,美國的女性乳腺癌發(fā)生率在所有惡性癌癥中排在第一位,致死率排在第二位,僅次于肺癌。盡管隨著各種診斷手段以及醫(yī)療手段的顯著提高,乳腺癌患者的發(fā)生率以及死亡率有逐年下降的的趨勢。但每年(包括2013)還有超過百萬的女性癌癥患者死于乳腺癌。乳腺癌原位腫瘤的生長并不是導(dǎo)致患者死亡的主要原因。研究表明,90%以上的乳腺癌患者發(fā)生死亡的主要原因是發(fā)生了腫瘤轉(zhuǎn)移。盡管在市場上已經(jīng)有許多治療乳腺癌的藥物,但是治療乳腺癌的新型藥物特別是針對乳腺癌轉(zhuǎn)移的藥物研究和開發(fā)也是十分必要的。 本文的內(nèi)容主要介紹兩種小分子化合物(葫蘆素E和組蛋白去乙�；敢种�,YF479)抗乳腺癌臨床前活性的研究： 第一部分：葫蘆素E (CuE)通過靶向抑制乳腺癌細胞的遷移和侵襲來抑制乳腺癌的轉(zhuǎn)移。CuE是從葫蘆科植物中提取出的一種四環(huán)三萜類小分子化合物。已有的研究發(fā)現(xiàn),CuE具有消炎、抗病毒、抗癌癥、抗血管新生等功能。但是在抑制乳腺癌轉(zhuǎn)移方面的研究還沒有任何報道。在動物實驗中,我們發(fā)現(xiàn)CuE能顯著地抑制乳腺癌轉(zhuǎn)移。體外的遷移和侵襲實驗結(jié)果表明葫蘆素能夠顯著地抑制乳腺癌細胞的遷移和侵襲。免疫組化(IHC)的實驗表明CuE在體內(nèi)對乳腺癌細胞的增殖和凋亡沒有任何作用。這也就說明,CuE抑制乳腺癌的轉(zhuǎn)移主要通過抑制腫瘤細胞的遷移和侵襲。對其抑制轉(zhuǎn)移的機制研究表明,CuE能夠阻止微絲的聚合,降低Arp3的表達。同時發(fā)現(xiàn)過表達Arp3可以延緩CuE所引起的微絲的解聚。FAK/MMPs信號通路在侵襲和轉(zhuǎn)移中起著關(guān)鍵的作用。我們研究發(fā)現(xiàn)CuE能夠抑制Src/FAK/Rac1/MMPs信號通路。綜合研究結(jié)果,我們認為CuE是一個治療乳腺癌轉(zhuǎn)移的潛在候選藥物。 第二部分：我們鑒定一種新型的組蛋白去乙�；敢种苿�(HDACi)YF479。研究發(fā)現(xiàn)YF479能夠抑制乳腺癌的生長、轉(zhuǎn)移和復(fù)發(fā)。傳統(tǒng)意義上,腫瘤是一種基因遺傳病,而近年來研究表明,表觀遺傳的改變比如甲基化、乙酰化、泛素化、糖基化等一系列的蛋白質(zhì)修飾也會引起腫瘤的發(fā)生。由于這種表觀遺傳的改變是一種可逆的過程,這就使得蛋白質(zhì)修飾的抑制劑用來治療腫瘤成為可能。組蛋白的乙酰化和去乙酰在正常的細胞中是處于平衡狀態(tài)的,分別由組蛋白去乙�；�(HDAC)以及組蛋白乙�；D(zhuǎn)移酶(HAT)調(diào)控。研究表明HDAC在乳腺癌異常表達,并可以作為治療的分子靶點。我們利用酶活試劑盒篩選我們實驗室潛在HDACi小分子庫,鑒定出一個新型的HDACi, YF479。我們發(fā)現(xiàn)YF479能夠顯著地誘導(dǎo)H3和H4乙�；Ｔ诩毎麑嶒炛�,我們發(fā)現(xiàn)YF479能夠誘導(dǎo)細胞的凋亡并引起細胞周期的阻滯。細胞克隆形成實驗也顯示YF479能顯著抑制乳腺癌細胞的克隆形成。體外黏附、遷移和侵襲實驗表明YF479能抑制腫瘤細胞的黏附、遷移和侵襲。體內(nèi)實驗也證實YF479能抑制乳腺癌的生長轉(zhuǎn)移和復(fù)發(fā),并能夠顯著提高小鼠的生存率。提示YF479是一個治療乳腺癌的潛在藥物。
[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.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R737.9

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本文編號：1936304