本文選題：青蒿酯　切入點(diǎn)：前列腺癌　出處：《南京醫(yī)科大學(xué)》2017年博士論文

【摘要】：前列腺癌(Prostatic cancer,PCa)是男性最常見的惡性腫瘤之一,在惡性腫瘤的死亡率上排在前列。眾所周知,前列腺癌對(duì)雄激素敏感,雄激素與前列腺癌細(xì)胞上的雄激素受體(androgenreceptor,AR)相結(jié)合可以促進(jìn)腫瘤進(jìn)展。雄激素去勢(shì)療法是目前治療前列腺癌的標(biāo)準(zhǔn)療法,在早期可以有效的抑制腫瘤生長(zhǎng)。但2～3年內(nèi),腫瘤會(huì)復(fù)發(fā)或進(jìn)展,形成去勢(shì)抵抗性前列腺癌。目前關(guān)于雄激素去勢(shì)療法治療后去勢(shì)抵抗性前列腺癌發(fā)生發(fā)展機(jī)制研究的文獻(xiàn)較多(其中包括類固醇激素代謝的變化、雄激素受體基因的擴(kuò)增或過(guò)表達(dá)、雄激素受體輔助調(diào)節(jié)因子、雄激素受體剪接變異體、生長(zhǎng)因子和/或細(xì)胞因子、雄激素受體突變等等機(jī)制)。目前普遍認(rèn)為在去勢(shì)抵抗性前列腺癌中,雄激素和雄激素受體在其發(fā)生發(fā)展中起到了關(guān)鍵的作用。青蒿酯(Artesunate,ART)是從中藥青篙中提取的有過(guò)氧基團(tuán)的倍半萜內(nèi)酯藥物,是傳統(tǒng)有效的抗瘧藥物。經(jīng)過(guò)多年的研究,青蒿酯除了抗瘧的作用,還具有明顯的抗腫瘤作用。它對(duì)誘導(dǎo)腫瘤細(xì)胞凋亡、抑制腫瘤細(xì)胞增值、調(diào)控DNA甲基化轉(zhuǎn)移酶及致癌基因和抑癌基因之間平衡等都有重要的作用。而且,青蒿酯和常規(guī)化療藥物相比,副作用較小,沒有交叉耐藥。研究發(fā)現(xiàn),ART對(duì)前列腺癌細(xì)胞具有抑制作用,但是具體的作用機(jī)制尚不明確。DNA甲基化是哺乳動(dòng)物中常見的基因組復(fù)制后的修飾。在人類多多種生理過(guò)程中扮演著重要的角色。DNA甲基化轉(zhuǎn)移酶(DNAmethyltransderase enzymes,DNMTs)是DNA甲基化的主要調(diào)節(jié)酶。研究發(fā)現(xiàn),DNMT3b在人類腫瘤的發(fā)生和發(fā)展中起到一定的作用。本研究的主要目的是通過(guò)ART與AR的相互作用來(lái)推斷ART對(duì)前列腺癌細(xì)胞的作用機(jī)制。體外細(xì)胞試驗(yàn)及動(dòng)物試驗(yàn)均采用22RV1前列腺癌細(xì)胞株。使用MTT實(shí)驗(yàn)測(cè)試細(xì)胞活性,用TUNEL實(shí)驗(yàn)測(cè)試細(xì)胞凋亡程度。試驗(yàn)中測(cè)試細(xì)胞AR及DNA甲基化轉(zhuǎn)移酶(DNAmethyltransderase enzymes,DNMTs)的表達(dá)變化。在22RV1細(xì)胞株的體外及動(dòng)物試驗(yàn)中發(fā)現(xiàn),ART可劑量依賴型地抑制前列腺癌細(xì)胞的生長(zhǎng)及活性;促進(jìn)PCa細(xì)胞的凋亡;降低PCa細(xì)胞AR的表達(dá);增加DNMTsb及其催化物的表達(dá)。進(jìn)一步研究發(fā)現(xiàn),AR可以下調(diào)DNMT3b的表達(dá);增加AR表達(dá)或者干擾DNMT3b可以對(duì)抗ART誘導(dǎo)的細(xì)胞毒作用及凋亡作用。然而,高表達(dá)DNMT3b不能改變ART對(duì)PCa細(xì)胞的效果。由此,我們推斷,ART通過(guò)AT-DNMT3b通路來(lái)抑制PCa細(xì)胞生長(zhǎng)。ART有可能成為抗前列腺癌的新藥。
[Abstract]:Prostate cancer prostatic cancer is one of the most common malignant tumors in men, leading the mortality rate. Prostate cancer is known to be sensitive to androgen. Androgen ovariectomies, the standard therapy for prostate cancer at present, can effectively inhibit tumor growth at an early stage, but within 2 to 3 years, androgen ovariectomies are associated with tumor progression. The tumor will recur or progress, forming ovariectomized prostate cancer. There are many literatures on the mechanism of development of ovariectomized prostate cancer after androgen castration therapy (including the changes of steroid hormone metabolism. Amplification or overexpression of androgen receptor genes, androgen receptor coregulation factors, androgen receptor splicing variants, growth factors and / or cytokines, Androgen receptor mutation and so on. It is widely believed that in ovariectomized prostate cancer, Androgen and androgen receptor play a key role in its development. Artesunate ART, a sesquiterpene lactone with peroxy group, is a traditional effective antimalarial drug, which has been studied for many years. Artemisia annua has obvious anti-tumor effect in addition to its antimalarial effect. It can induce apoptosis of tumor cells and inhibit the proliferation of tumor cells. Regulation of the balance between DNA methyltransferase and oncogenes and tumor suppressor genes plays an important role. Moreover, Artemisia annua has less side effects than conventional chemotherapeutic drugs. There is no cross resistance. Studies have found that art has an inhibitory effect on prostate cancer cells. However, the specific mechanism of DNA methylation is not clear. DNA methylation is a common genome modification in mammals. It plays an important role in many physiological processes of human. DNA methyltransferase DNA methyltransderase transmenses (DNMTs) is DNA methylation. It is found that DNMT3b plays an important role in the occurrence and development of human tumors. The main purpose of this study is to infer the mechanism of ART action on prostate cancer cells through the interaction of ART and AR. 22RV1 prostate cancer cell line was used in cell test and animal test. Cell activity was tested by MTT assay. The apoptosis degree was measured by TUNEL assay. The expression of AR and DNA methyltransderase transducers (DNMTs) were measured. In vitro and in animal experiments, it was found that art could inhibit the growth and activity of prostate cancer cells in a dose-dependent manner. Promote the apoptosis of PCa cells, decrease the expression of AR in PCa cells, increase the expression of DNMTsb and its catalysts. Increasing AR expression or interfering with DNMT3b can antagonize the cytotoxicity and apoptosis induced by ART. However, high expression of DNMT3b can not change the effect of ART on PCa cells. We infer that art may be a new anti-prostate cancer drug to inhibit the growth of PCa cells through the AT-DNMT3b pathway.
【學(xué)位授予單位】：南京醫(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)】：R737.25

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