本文選題：丙戊酸 + 羥基脲��； 參考：《山東大學(xué)》2016年碩士論文

【摘要】：目的乳腺癌作為一種女性常見的惡性腫瘤,已成為世界婦女健康的共同威脅�；瘜W(xué)藥物一直是臨床腫瘤的主要治療方法,但化療藥物自身的副作用以及長(zhǎng)期應(yīng)用后腫瘤細(xì)胞的抗藥性使其臨床應(yīng)用受到了極大地限制。因此,臨床上迫切需要一種新型的抗腫瘤藥物或更有效的治療策略用于腫瘤患者的治療。近些年來,組蛋白去乙�；敢种苿�(histone deacetylase inhibitors, HDACi)被廣泛的研究,并已經(jīng)作為一種新型的抗腫瘤細(xì)胞生長(zhǎng)藥物進(jìn)入臨床試驗(yàn)研究階段。我們和其他研究小組的實(shí)驗(yàn)結(jié)果都證明組蛋白去乙�；敢种苿┲幸环N代表性藥物,丙戊酸(Valproic acid, VPA),可抑制乳腺癌細(xì)胞的生長(zhǎng),但其抗腫瘤作用的機(jī)制目前還不十分清楚。此外,我們課題組既往研究還證明DNA復(fù)制蛋白A2高度磷酸化(RPA2-p)-介導(dǎo)的同源重組(Homologous Recombination, HR)通路可特異地參與羥基脲(hydroxyurea, HU)-誘導(dǎo)的DNA復(fù)制阻滯的修復(fù)過程。為此,本課題擬重點(diǎn)探討VPA是否通過干擾RPA2-p介導(dǎo)的HR修復(fù)通路而造成DNA復(fù)制障礙,進(jìn)而達(dá)到抑制腫瘤細(xì)胞生長(zhǎng)的作用；更為重要的是,HU也是臨床上常用的抗腫瘤藥物,為指導(dǎo)VPA與HU聯(lián)合用藥治療腫瘤患者提供有力的理論和實(shí)驗(yàn)依據(jù)。方法1.細(xì)胞克隆形成實(shí)驗(yàn)觀察兩種藥物對(duì)乳腺癌細(xì)胞系MCF7細(xì)胞存活的影響單獨(dú)VPA組用0.5mM的VPA作用MCF7細(xì)胞24或48h；單獨(dú)HU組用2mMHU作用MCF7細(xì)胞18h；聯(lián)合用藥組用0.5mM的VPA預(yù)處理24或48h,換2mMHU和0.5mM VPA混合液作用MCF7細(xì)胞18h后,換新鮮培養(yǎng)基繼續(xù)培養(yǎng)14天,計(jì)算克隆形成率。2.彗星實(shí)驗(yàn)檢測(cè)兩種藥物對(duì)細(xì)胞核DNA的損傷情況用0.5mM VPA作用MCF7細(xì)胞24h、 2mMHU作用細(xì)胞18h或兩藥聯(lián)合作用細(xì)胞,收集各組細(xì)胞制成單細(xì)胞懸液后進(jìn)行彗星實(shí)驗(yàn),觀察細(xì)胞拖尾情況。3.DNA雙鏈斷裂標(biāo)志物yH2AX焦點(diǎn)形成和HR機(jī)制中關(guān)鍵蛋白R(shí)PA2-p和Rad51表達(dá)水平的檢測(cè)用0.5mM VPA作用MCF7細(xì)胞24h、2mMHU作用細(xì)胞18h或兩藥聯(lián)合作用細(xì)胞。利用免疫熒光技術(shù),將各組細(xì)胞固定后觀察細(xì)胞核內(nèi)yH2AX、 RPA2-p和Rad51焦點(diǎn)形成情況;再利用免疫印跡實(shí)驗(yàn),收集各實(shí)驗(yàn)組細(xì)胞的蛋白裂解液檢測(cè)RPA2-p和Rad51蛋白的表達(dá)水平。4.流式細(xì)胞儀檢測(cè)兩種藥物對(duì)細(xì)胞DNA損傷后修復(fù)效率的影響首先對(duì)MCF7細(xì)胞進(jìn)行轉(zhuǎn)染,把帶有標(biāo)記綠色熒光蛋白的同源底物pDR-GFP轉(zhuǎn)染入細(xì)胞內(nèi)進(jìn)行篩選,建立穩(wěn)定表達(dá)同源底物pDR-GFP的MCF7細(xì)胞系。然后對(duì)含同源底物pDR-GFP的MCF7細(xì)胞分別進(jìn)行單獨(dú)0.5mM VPA作用24或48h、單獨(dú)2mMHU作用18h或兩藥聯(lián)合處理后,收集單細(xì)胞懸液,利用流式細(xì)胞術(shù)測(cè)定藥物對(duì)細(xì)胞HR修復(fù)效率的影響。結(jié)果1.在HU-誘導(dǎo)的DNA復(fù)制阻滯中,VPA增加了細(xì)胞內(nèi)DNA雙鏈斷裂損傷的蓄積免疫熒光實(shí)驗(yàn)結(jié)果顯示,對(duì)照組細(xì)胞核內(nèi)yH2AX焦點(diǎn)陽(yáng)性率為10.52%。0.5mM VPA作用于MCF7細(xì)胞后,與對(duì)照組相比,細(xì)胞核內(nèi)yH2AX焦點(diǎn)陽(yáng)性率有增加趨勢(shì),但差異無統(tǒng)計(jì)學(xué)意義(P0.05)。而2mM HU單獨(dú)作用MCF7細(xì)胞可引起細(xì)胞核內(nèi)γH2AX焦點(diǎn)陽(yáng)性率出現(xiàn)顯著增加,一些陽(yáng)性率比較高的細(xì)胞內(nèi)γH2AX焦點(diǎn)融合成片,與對(duì)照組相比陽(yáng)性率約升高3.5倍(P0.01)。兩藥聯(lián)合作用后,細(xì)胞核γH2AX焦點(diǎn)陽(yáng)性率與對(duì)照組相比增加近5倍(P0.01),分別是單獨(dú)VPA或HU組陽(yáng)性率的3.83或1.33倍。彗星實(shí)驗(yàn)結(jié)果顯示,與對(duì)照組相比,單獨(dú)0.5mM VPA或2mMHU作用細(xì)胞后均可引起彗星拖尾長(zhǎng)度的增加(P0.01),且HU組彗星拖尾比VPA組要更長(zhǎng)一些(P0.01)；VPA和HU聯(lián)合作用后,彗星拖尾長(zhǎng)度與對(duì)照組相比增加了74.44%(P0.01),同時(shí)也比單藥組細(xì)胞的彗星拖尾長(zhǎng)度長(zhǎng)(P0.01)。2.在HU-介導(dǎo)的復(fù)制阻滯中,VPA抑制了同源重組修復(fù)分子機(jī)制免疫熒光實(shí)驗(yàn)結(jié)果顯示,對(duì)照組帶有γH2AX焦點(diǎn)的細(xì)胞陽(yáng)性率為6.64%；單獨(dú)0.5mM VPA或2mM HU作用組,yH2AX焦點(diǎn)陽(yáng)性率分別降為9.19%或20.92%,各單藥處理組細(xì)胞核內(nèi)yH2AX焦點(diǎn)的陽(yáng)性率比對(duì)照組仍舊要高(P0.01),而兩藥聯(lián)合作用組的焦點(diǎn)陽(yáng)性率更高,為34.92%。利用表達(dá)同源底物pDR-GFP的MCF7細(xì)胞,通過流式細(xì)胞術(shù)測(cè)定藥物對(duì)細(xì)胞HR修復(fù)效率的影響。實(shí)驗(yàn)結(jié)果顯示,對(duì)照組細(xì)胞HR修復(fù)效率為85×10-6；單獨(dú)VPA作用后,細(xì)胞的HR修復(fù)效率降為65×10-5(P0.05)；單獨(dú)HU作用,HR修復(fù)效率顯著升高,上升為148×10-6(P0.01)；而VPA和HU兩藥聯(lián)合作用后,與單獨(dú)HU相比,細(xì)胞HR修復(fù)效率出現(xiàn)了明顯的下降,為100×10-6(P0.01)。3.在HU-介導(dǎo)的復(fù)制阻滯中,VIA抑制了RPA2-p和Rad51的功能免疫印跡和免疫熒光實(shí)驗(yàn)結(jié)果均顯示,未處理組和單獨(dú)VPA處理組細(xì)胞均未檢測(cè)到細(xì)胞核內(nèi)RPA2-p的表達(dá)；HU作用于細(xì)胞后,細(xì)胞核內(nèi)RPPA2-p表達(dá)和焦點(diǎn)陽(yáng)性率顯著增加；聯(lián)合VPA作用后,與單獨(dú)HU組相比,細(xì)胞核內(nèi)RPA2-p的表達(dá)和焦點(diǎn)陽(yáng)性率出現(xiàn)顯著降低(P0.01)。蛋白質(zhì)免疫印跡實(shí)驗(yàn)結(jié)果顯示,各處理組細(xì)胞Rad51蛋白表達(dá)量基本一致,無顯著性差異(P0.05)。但是,免疫熒光實(shí)驗(yàn)檢測(cè)到對(duì)照組細(xì)胞核內(nèi)Rad51焦點(diǎn)陽(yáng)性率為24.74%; 0.5mMVPA處理MCF7細(xì)胞后,與對(duì)照組相比細(xì)胞核內(nèi)Rad51焦點(diǎn)陽(yáng)性率有一定程度降低(P0.01); 2mMHU作用18h后,細(xì)胞核內(nèi)Rad51焦點(diǎn)顯著升高；而2mMHU聯(lián)合0.5mM VPA作用組細(xì)胞的Rad51焦點(diǎn)陽(yáng)性率與HU組相比出現(xiàn)明顯下降(P0.01),大約降到40%左右。Rad51和RPA2-p焦點(diǎn)不僅能夠較好的共定位與細(xì)胞核內(nèi),而且各處理組細(xì)胞核內(nèi)Rad51和RPA2-p焦點(diǎn)陽(yáng)性率都非常接近。4.VPA能增加腫瘤細(xì)胞對(duì)HU的敏感性,兩藥聯(lián)合對(duì)腫瘤細(xì)胞具有協(xié)同殺傷作用細(xì)胞克隆形成實(shí)驗(yàn)結(jié)果顯示,與對(duì)照組相比,單獨(dú)0.5mM的VPA作用MCF7細(xì)胞24或48h后,細(xì)胞存活率分別下降21.55%(P0.01)和30.17%(P0.01)；單獨(dú)2mM的HU作用細(xì)胞18h后,細(xì)胞存活率下降61.21%(P0.01)；而2mMHU和0.5mM VPA聯(lián)合作用細(xì)胞后,細(xì)胞存活率顯著降低,約下降80%(P0.01)。進(jìn)一步將實(shí)驗(yàn)結(jié)果進(jìn)行校正后,與校正前趨勢(shì)相一致。說明不但單獨(dú)VPA或HU能抑制細(xì)胞生長(zhǎng),VPA和HU兩藥聯(lián)合對(duì)MCF7細(xì)胞有協(xié)同殺傷作用�？寺⌒纬蓪�(shí)驗(yàn)結(jié)果進(jìn)一步顯示,將MCF7細(xì)胞內(nèi)RPA2的磷酸化位點(diǎn)突變(muRPA2)后,在應(yīng)答HU損傷時(shí),與wtRPA2細(xì)胞相比,muRPA2細(xì)胞的存活率下降至42.58%(P0.01),提示滅活RPA2磷酸化通路可增加細(xì)胞對(duì)HU的敏感性；如果wtRPA2細(xì)胞經(jīng)VPA預(yù)處理后,與未經(jīng)VPA處理的細(xì)胞相比,細(xì)胞存活率下降了37.82%(P0.01),這一變化與muRPA2細(xì)胞對(duì)HU損傷應(yīng)答有相同趨勢(shì)；但是muRPA2細(xì)胞經(jīng)VPA預(yù)處理后,與其無VPA處理組細(xì)胞相比,細(xì)胞存活率僅下降了15.69%(P0.01)。以上結(jié)果進(jìn)一步確認(rèn)VPA抑制細(xì)胞生長(zhǎng)是通過干擾RPA2-p介導(dǎo)的DNA修復(fù)通路實(shí)現(xiàn)的。5.VPA與PARP抑制劑聯(lián)合應(yīng)用對(duì)腫瘤細(xì)胞具有協(xié)同殺傷作用克隆形成實(shí)驗(yàn)結(jié)果顯示,VPA或ABT888作用于MCF7細(xì)胞后都可以造成細(xì)胞存活率的顯著降低(P0.01)；兩藥聯(lián)合作用組的細(xì)胞存活率下降更為顯著。聯(lián)合作用組的存活率不僅明顯低于對(duì)照組(P0.01),而且相對(duì)于VPA或ABT888單獨(dú)作用組也有顯著的降低(P0.01),實(shí)驗(yàn)結(jié)果進(jìn)一步確認(rèn)VPA能夠干擾HR修復(fù)通路。結(jié)論1.在DNA復(fù)制阻斷條件下,安全劑量VPA可引起更多的DNA雙鏈斷裂損傷的蓄積。2.安全劑量VPA可通過干擾PA2p-Rad51介導(dǎo)的HR修復(fù)通路造成DNA復(fù)制障礙,從而抑制腫瘤細(xì)胞的生長(zhǎng)。3.安全劑量VPA能增加腫瘤細(xì)胞對(duì)HU的敏感性,VPA和HU聯(lián)合用藥對(duì)抑制乳腺癌MCF7細(xì)胞的生長(zhǎng)起到協(xié)同作用。
[Abstract]:Objective breast cancer, as a common malignant tumor of women, has become a common threat to the health of women in the world. Chemical drugs have always been the main treatment for clinical tumors. However, the side effects of chemotherapy drugs and the drug resistance of cancer cells after long-term application have greatly restricted their clinical application. Therefore, it is urgently needed in clinic. In recent years, histone deacetylase inhibitors (HDACi) has been widely studied and has been used as a new type of antitumor cell growth drug into clinical trials. The results of the group have proved that a representative drug of histone deacetylase inhibitor, Valproic acid (VPA), can inhibit the growth of breast cancer cells, but the mechanism of its anti-tumor effect is not yet very clear. In addition, our group has previously studied the high phosphorylation of DNA replicin A2 (RPA2-p) - mediate Homologous Recombination (HR) pathway can participate in the repair process of hydroxyurea (hydroxyurea, HU) - induced DNA replication. To this end, this topic intends to focus on whether VPA obstructs the growth of tumor cells by interfering with the HR repair pathway mediated by RPA2-p and thus to inhibit the growth of tumor cells. It is important that HU is also a clinically commonly used antitumor drug, providing a powerful theoretical and experimental basis for guiding the combination of VPA and HU in the treatment of cancer patients. Method 1. cell clone formation experiments were conducted to observe the effects of two drugs on the survival of MCF7 cells in breast cancer cell lines alone. The VPA action of 0.5mM was used in the VPA group of MCF7 cells 24 or 48h; a single HU group was used. The MCF7 cell 18h was treated with 2mMHU, the combination group pretreated 24 or 48h with VPA of 0.5mM, and the 2mMHU and 0.5mM VPA mixture acted on MCF7 cell 18h, and then the fresh medium continued to be cultured for 14 days. 18h or two drugs combined cells, collecting cells from each group and making a single cell suspension to conduct a comet experiment, observing the formation of the.3.DNA double strand break marker yH2AX focus and the detection of the key protein RPA2-p and Rad51 expression levels in the HR mechanism by using 0.5mM VPA as MCF7 cell 24h, 2mMHU acting cell 18h or two drugs. Cell. Using immunofluorescence technique to observe the formation of yH2AX, RPA2-p and Rad51 focal points in the nucleus after immobilization, and then use immunoblotting experiment to collect the expression level of RPA2-p and Rad51 protein in the cells of each experimental group by.4. flow cytometry to detect the effect of two kinds of drugs on the repair efficiency after the cell DNA damage. The MCF7 cells were transfected first, and the homologous substrate pDR-GFP with the labeled green fluorescent protein was transfected into the cell, and the MCF7 cell line that expressed the homologous substrate pDR-GFP was established. Then, the MCF7 cells containing the homologous substrate pDR-GFP were separately used as 0.5mM VPA for 24 or 48h, and the single 2mMHU action 18h or two drug combinations were used. After collecting single cell suspension and using flow cytometry to determine the effect of drug on cell HR repair efficiency. Results 1. in HU- induced DNA replication block, VPA increased the accumulation of DNA double strand breaks in cell immunofluorescence test results, and the positive rate of yH2AX focus in the nucleus was 10.52%.0.5mM VPA in MCF7 cells in the control group. Compared with the control group, the positive rate of yH2AX focus in the nucleus increased, but the difference was not statistically significant (P0.05), but the positive rate of 2mM HU alone in MCF7 cells could cause a significant increase in the positive rate of the gamma H2AX focus in the nucleus. Some positive rates of intracellular gamma H2AX focal points were fused into slices, and the positive rate was about 3.5 higher than that of the control group. P0.01. After the combination of two drugs, the positive rate of the nucleus gamma H2AX focus increased nearly 5 times compared with the control group (P0.01), which was 3.83 or 1.33 times the positive rate of the single VPA or HU group respectively. The comet experiment showed that compared with the control group, 0.5mM VPA or 2mMHU acting cells could cause the increase of the tail length of the comet (P0.01), and the HU group comet. The tail was longer than the VPA group (P0.01); after the combination of VPA and HU, the tail length of comets increased by 74.44% (P0.01) compared with the control group. Meanwhile, the length of the comet tail was longer than that of the single drug group (P0.01).2. in HU- mediated replication block, and VPA inhibited the results of the molecular mechanism immunofluorescence test of the homologous regroup and the control group. The positive rate of cells with gamma H2AX focus was 6.64%, and the positive rate of yH2AX focus decreased to 9.19% or 20.92% respectively in the group of 0.5mM VPA or 2mM HU, and the positive rate of yH2AX focus in the nucleus of each single drug treatment group was higher than that of the control group (P0.01), while the positive rate of the focal point in the two drug combination group was higher, and the expression of the homologous substrate pDR for 34.92%. was used for 34.92%.. The effect of -GFP MCF7 cells on the efficiency of HR repair was measured by flow cytometry. The experimental results showed that the efficiency of HR repair in the control group was 85 x 10-6, and the efficiency of HR repair was reduced to 65 * 10-5 (P0.05) after the action of VPA alone; the efficiency of HR repair was significantly increased and increased to 148 x 10-6 (P0.01) by the action of HU, while VPA and HU two were used. After the combined action, the HR repair efficiency of cells decreased significantly compared with the single HU, which was 100 * 10-6 (P0.01).3. in HU- mediated replication block. VIA inhibited the functional immunoblotting and immunofluorescence results of RPA2-p and Rad51, and the expression of RPA2-p in the untreated and isolated VPA cells was not detected. After the action of HU on the cells, the expression of RPPA2-p and the positive rate of the focal point in the nucleus increased significantly, and the expression of RPA2-p and the positive rate of the focus in the nucleus were significantly lower than that of the single HU group after the action of VPA (P0.01). The results of protein immunoblotting showed that the expression of Rad51 protein in the cells of each treatment group was basically the same, and there was no significant difference. P0.05. However, the immunofluorescence test showed that the positive rate of Rad51 focus in the nucleus of the control group was 24.74%. After 0.5mMVPA treatment of MCF7 cells, the positive rate of Rad51 focus in the nucleus was reduced to a certain degree (P0.01). After 2mMHU action 18h, the Rad51 focus in the nucleus increased significantly; 2mMHU combined with 0.5mM VPA group cells. The positive rate of Rad51 focus decreased significantly compared with that of the HU group (P0.01), which decreased to about 40%.Rad51 and RPA2-p focus not only in the co localization and in the nucleus, but also in the nucleus Rad51 and RPA2-p foci in each treatment group, which were very close to.4.VPA to increase the sensitivity of the tumor cells to HU. The two drugs combined with the tumor cells. Experimental results showed that the cell survival rate decreased by 21.55% (P0.01) and 30.17% (P0.01) after MCF7 cells of MCF7 cells 24 or 48h respectively compared with the control group, compared with the control group, and the cell survival rate decreased by 61.21% (P0.01) after 18h in 2mM alone, while 2mMHU and 0.5mM cells were combined to act on cells. The cell survival rate decreased significantly, about 80% (P0.01). Further, the experimental results were corrected, and the results were in accordance with the pre correction trend. It was shown that not only VPA or HU alone could inhibit cell growth, but the VPA and HU two drugs have synergistic killing effect on MCF7 cells. The cloning and formation of experimental results showed that the phosphorylation site of RPA2 in MCF7 cells was a step. After muRPA2, the survival rate of muRPA2 cells decreased to 42.58% (P0.01) in response to HU damage compared with wtRPA2 cells, suggesting that the inactivated RPA2 phosphorylation pathway increased the cell's sensitivity to HU; if wtRPA2 cells were pretreated with VPA, the cell survival rate decreased by 37.82% (P0.01) compared with those without VPA, and this change was associated with muRP. The response of A2 cells to HU damage response was the same, but the cell survival rate of muRPA2 cells was only 15.69% (P0.01) compared with those without VPA treatment group after VPA pretreatment. The results further confirmed that the growth of VPA suppressor cells was combined with.5.VPA and PARP inhibitors that interfered with RPA2-p mediated DNA repair pathway. The results of the synergistic killing cloning of the tumor cells showed that VPA or ABT888 could significantly decrease the cell survival rate (P0.01) after the action of MCF7 cells, and the cell survival rate of the two drug combined group decreased significantly. The survival rate of the combined group was not only lower than that of the control group (P0.01), but also relative to VPA or ABT88. 8 the single action group also had a significant decrease (P0.01). The experimental results further confirmed that VPA could interfere with the HR repair pathway. Conclusion under the condition of DNA replication, the safe dose VPA can cause more.2. safe dose of DNA double strand break damage, VPA can cause DNA replication obstacle by interfering PA2p-Rad51 mediated HR repair pathway, thus inhibiting the DNA replication disorder. The growth of.3., a safe dose of VPA, can increase the sensitivity of tumor cells to HU, and the combination of VPA and HU plays a synergistic role in inhibiting the growth of MCF7 cells in breast cancer.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R730.5

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