本文選題：替莫唑胺 + 雌激素受體β激動劑　； 參考：《吉林大學(xué)》2016年博士論文

【摘要】：研究背景:替莫唑胺(Temozolomide,TMZ)是一種新型咪唑四嗪類烷化劑,在生理環(huán)境可以通過非酶途徑快速轉(zhuǎn)化為活性化合物,并通過誘導(dǎo)DNA甲基化來促進(jìn)腫瘤細(xì)胞凋亡。TMZ吸收迅速,易于透過血腦屏障,并具有良好的抗膠質(zhì)瘤活性,因此在中樞神經(jīng)系統(tǒng)腫瘤特別是惡性膠質(zhì)瘤化療中得到了廣泛的應(yīng)用。然而腫瘤細(xì)胞對TMZ的耐藥性經(jīng)常發(fā)生,是臨床上化療失敗的主要原因。因此,如何解決TMZ耐藥、增加惡性膠質(zhì)瘤細(xì)胞對TMZ的敏感性已成為神經(jīng)外科臨床醫(yī)生及研究人員的最新關(guān)注熱點(diǎn)問題。雌激素受體β是一種與神經(jīng)細(xì)胞發(fā)育和分化有關(guān)的多功能蛋白,具備抑癌基因活性,其表達(dá)水平的變化與神經(jīng)膠質(zhì)瘤的發(fā)生發(fā)展有著密切的關(guān)系。甘草素(Liquiritigenin,Liq)是存在于豆科植物甘草(Glycyrrhiza uralensis Fisch)中的二氫黃酮單體化合物,是一種天然的雌激素受體β(estrogen receptor,ERβ)激動劑。前期試驗(yàn)發(fā)現(xiàn)Liq能抑制多種腫瘤如乳腺癌、宮頸癌的增殖,同時具備增加化療藥物的敏感性,預(yù)防腫瘤復(fù)發(fā)的功效。本課題擬從體內(nèi)和體外兩個方面觀察Liq對TMZ抗神經(jīng)膠質(zhì)瘤治療效果的影響,探討Liq、TMZ聯(lián)合使用在臨床應(yīng)用方面的優(yōu)越性;同時深入研究Liq增加腫瘤細(xì)胞對TMZ敏感性的分子基礎(chǔ),為Liq在膠質(zhì)瘤治療方面的重要作用提供理論基礎(chǔ)和實(shí)驗(yàn)依據(jù)。方法:研究分體內(nèi)、體外兩個部分。體外研究我們選用了三種人神經(jīng)膠質(zhì)瘤細(xì)胞株:對TMZ低敏感性的U138,對TMZ高敏感性的U251以及TMZ耐藥細(xì)胞株T98G,采用MTT法、流式細(xì)胞術(shù)法檢測不同濃度的Liq單獨(dú)使用或者與TMZ聯(lián)用在體外對膠質(zhì)瘤細(xì)胞增殖、凋亡和細(xì)胞周期的影響;采用Western Blot方法檢測Liq和TMZ作用后ERβ、MGMT、Caspase-3、Akt、p-AKT、P70S6K、p-P70S6K等凋亡因子和信號分子蛋白表達(dá)水平及磷酸化水平的變化;采用RNA干擾的方法沉默ERβ的表達(dá),明確Liq對PI3K/AKT/m TOR信號通路影響的機(jī)制;聯(lián)合使用PI3K/AKT/m TOR通路抑制劑和激活劑,進(jìn)一步探討Liq對該通路的調(diào)控作用以及促進(jìn)TMZ敏感性的分子機(jī)制。體內(nèi)研究采用裸鼠膠質(zhì)瘤模型作為研究對象,在裸鼠左腹皮下接種U138膠質(zhì)瘤細(xì)胞(106/100μl)后,分為四組:對照組(DMSO),TMZ組(50 mg/kg/d),Liq組(30 mg/kg/d)以及聯(lián)合組(TMZ 50 mg/kg/d+Liq 30 mg/kg/d),每日進(jìn)行腹腔注射,觀察各組裸鼠腫瘤生長狀況,于接種移植瘤的30日處死裸鼠,在體內(nèi)水平研究Liq對ERβ表達(dá)的影響以及對TMZ抗腫瘤效果的協(xié)同作用。結(jié)果:一、體外實(shí)驗(yàn):膠質(zhì)瘤細(xì)胞U138經(jīng)過不同濃度的Liq(10、20、40、80、160和320μM)處理72 h后,細(xì)胞活性測試結(jié)果顯示Liq對U138有顯著的抑制作用,且伴隨濃度的增加其抑制作用逐漸增強(qiáng),呈現(xiàn)劑量依賴性效應(yīng)。其中80μM的Liq既可有效抑制U138細(xì)胞的活性,但又不會導(dǎo)致細(xì)胞的過度死亡,因此我們選用該濃度的Liq進(jìn)行后續(xù)研究。該濃度的Liq與不同濃度的TMZ(25、50、100、200、400和800μM)聯(lián)合使用后,可以顯著增加TMZ對U138增殖的抑制作用。當(dāng)100μM TMZ與80μM的Liq聯(lián)合處理72h后,U138腫瘤細(xì)胞存活率僅為50.36%,顯著低于單獨(dú)使用TMZ時腫瘤細(xì)胞的存活率(90.33%,P0.001),證明Liq可有效增強(qiáng)腫瘤細(xì)胞對TMZ的敏感性。流式細(xì)胞術(shù)細(xì)胞周期分析結(jié)果顯示,與TMZ單獨(dú)使用相比,聯(lián)合使用Liq可進(jìn)一步增強(qiáng)TMZ誘導(dǎo)的S期阻滯(64.63%vs 40.43%,P0.001),有效地抑制細(xì)胞進(jìn)入增殖期。Annexin V/PI雙染凋亡分析表明Liq和TMZ聯(lián)合使用可以顯著增加U138膠質(zhì)瘤細(xì)胞凋亡率(27.5%vs 18.6%,P0.001),增加凋亡標(biāo)志物Caspase-3剪切體的形成。Liq與TMZ的協(xié)同作用在另外兩種膠質(zhì)瘤細(xì)胞U251和T98G中也得到了驗(yàn)證。Western Blot檢測PI3K/AKT/m TOR通路的結(jié)果表明,Liq可以激活ERβ,降低AKT和P70S6K磷酸化水平,從而抑制PI3K/AKT/m TOR信號通路的活性,但對腫瘤耐藥基因MGMT并沒有直接的影響。通過RNA干擾沉默ERβ表達(dá)后,Liq喪失了對PI3K/AKT/m TOR通路的調(diào)控作用,說明Liq是通過激活ERβ來調(diào)節(jié)PI3K/AKT/m TOR通路活性的。PI3K/AKT/m TOR通路的抑制劑XL765可以明顯提高細(xì)胞對TMZ的敏感性,提示PI3K/AKT/m TOR通路的激活對神經(jīng)膠質(zhì)瘤細(xì)胞具有保護(hù)作用,從而拮抗TMZ的作用。聯(lián)合使用PI3K/AKT/m TOR激活劑IGF-1可以拮抗Liq介導(dǎo)的TMZ毒性,提示Liq是通過抑制PI3K/AKT/m TOR來發(fā)揮作用的。二、體內(nèi)實(shí)驗(yàn):結(jié)果顯示,對照組腫瘤平均體積為1.84±0.13cm3,單獨(dú)使用TMZ組腫瘤平均體積為0.93±0.11cm3,單獨(dú)使用Liq組腫瘤平均體積為1.34±0.15cm3,而聯(lián)合使用TMZ和Liq組腫瘤平均體積為0.36±0.04cm3。此結(jié)果與體外細(xì)胞實(shí)驗(yàn)結(jié)果相符,聯(lián)合應(yīng)用Liq和TMZ可以顯著抑制腫瘤生長,提高腫瘤對TMZ的敏感性,差異具有統(tǒng)計學(xué)意義(P0.05)。同時,Western Blot結(jié)果證明,Liq可以在體內(nèi)增加腫瘤細(xì)胞ERβ的表達(dá)量,推斷Liq可能在體內(nèi)通過激活ERβ及相關(guān)信號通路來達(dá)到抑制腫瘤生長,提高腫瘤細(xì)胞對TMZ敏感性的作用。實(shí)驗(yàn)結(jié)論:1.Liq可抑制膠質(zhì)瘤細(xì)胞(U138)增殖并明顯促進(jìn)其凋亡,可顯著增強(qiáng)腫瘤細(xì)胞對TMZ的敏感性;2.Liq通過特異性激活ERβ來抑制PI3K/AKT/m TOR信號通路的活性;3.Liq對TMZ的增敏功能依賴于其對PI3K/AKT/m TOR通路的抑制;4.體內(nèi)聯(lián)合使用Liq和TMZ處理荷瘤小鼠發(fā)現(xiàn)Liq顯著增加腫瘤細(xì)胞對TMZ的敏感性。以上實(shí)驗(yàn)結(jié)果提示Liq通過激活ERβ抑制PI3K/AKT/m TOR來促進(jìn)TMZ治療膠質(zhì)瘤的效應(yīng)。同時本研究也為其他ERβ激動劑可以作為一種有效的化療藥物用于神經(jīng)膠質(zhì)瘤的常規(guī)聯(lián)合治療提供了依據(jù)和線索。
[Abstract]:Background: Temozolomide (TMZ) is a new imidazole four alkyl alkylating agent, which can be transformed into active compound quickly by non enzyme pathway in physiological environment. By inducing DNA methylation to promote the rapid absorption of apoptosis.TMZ in tumor cells, it is easy to penetrate the blood brain barrier and has good antiglioma activity. The armature nervous system tumor, especially the malignant glioma, has been widely used in chemotherapy. However, the drug resistance of the tumor cells to TMZ often occurs, which is the main reason for the failure of the clinical chemotherapy. Therefore, how to solve the TMZ resistance and increase the sensitivity of malignant glioma cells to TMZ has become the latest in the Department of Neurosurgery clinicians and researchers The estrogen receptor beta is a multifunctional protein related to the development and differentiation of nerve cells and has the activity of tumor suppressor gene. The change of the expression level is closely related to the occurrence and development of glioma. Liquiritigenin (Liq) is found in the glycyrrhiza Glycyrrhiza (Glycyrrhiza uralensis Fisch). The two hydrogen flavone monomer compound is a natural estrogen receptor beta (estrogen receptor, ER beta) agonist. Earlier experiments showed that Liq could inhibit the proliferation of various tumors such as breast and cervix cancer, and also have the efficacy of increasing the sensitivity of chemotherapy drugs and preventing the recurrence of tumor. This subject is to observe the Liq to TMZ from the body and in vitro, in the body and in vitro. The effect of anti neuroglioma treatment, to explore the advantages of Liq, TMZ combined use in clinical application, and to further study the molecular basis of Liq to increase the sensitivity of tumor cells to TMZ, and to provide theoretical basis and experimental basis for the important role of Liq in the treatment of glioma. Methods: the study in the body and in vitro two parts. We selected three human glioma cell lines: TMZ low sensitivity U138, TMZ Gao Min sensitive U251 and TMZ resistant cell strain T98G, using MTT method, flow cytometry to detect the effects of the different concentrations of Liq alone or with TMZ on the proliferation, apoptosis and cell cycle of glioma cells in vitro; Western Blo. T was used to detect the changes in ER beta, MGMT, Caspase-3, Akt, p-AKT, P70S6K, p-P70S6K, and the level of protein expression and phosphorylation of signal molecules, such as ER beta, Akt, p-AKT, P70S6K, p-P70S6K, and the expression of ER beta by RNA interference. To further explore the regulatory effect of Liq on the pathway and the molecular mechanism to promote the sensitivity of TMZ, in vivo study of nude mice glioma model was used as the research object. After subcutaneous inoculation of U138 glioma cells (106/100 Mu L) in the left abdomen of nude mice, four groups were divided: the control group (DMSO), the TMZ group (50 mg/kg/d), the Liq group (30 mg/kg/d) and the TMZ 5 (TMZ 5). 0 mg/kg/d+Liq 30 mg/kg/d), daily intraperitoneal injection was carried out to observe the tumor growth status of nude mice in each group. The effects of Liq on the expression of ER beta and the synergistic effect on the anti tumor effect of TMZ were studied in vivo at 30 days after inoculation. Results: 1. In vitro experiment: the U138 cells were treated with different concentrations of Liq (10,20,40,80160) in vitro. After 320 M) treatment of 72 h, the results of cell activity test showed that Liq had a significant inhibitory effect on U138, and with the increase of concentration, the inhibitory effect gradually increased and showed a dose dependent effect. The Liq of 80 mu M could effectively inhibit the activity of U138 cells, but did not lead to excessive cell death. Therefore, we choose the Liq of this concentration. After the combined use of the concentration of Liq and different concentrations of TMZ (25,50100200400 and 800 u M), the inhibitory effect of TMZ on U138 proliferation was significantly increased. The survival rate of the tumor cells was only 50.36% when the 100 M TMZ and 80 micron Liq were combined with 72h, significantly lower than the survival rate of the tumor cells (90.33%, 01) Liq could effectively enhance the sensitivity of tumor cells to TMZ. Flow cytometry cell cycle analysis showed that combined use of Liq could further enhance TMZ induced S phase block (64.63%vs 40.43%, P0.001) compared with TMZ alone, and effectively inhibit the cell entering the proliferative.Annexin V/PI double staining apoptosis analysis showed that Liq and TMZ were combined. The use can significantly increase the apoptosis rate of U138 glioma cells (27.5%vs 18.6%, P0.001), and the synergistic effect of.Liq and TMZ on the formation of Caspase-3 shear body,.Liq and TMZ, in the other glioma cells, U251 and T98G, also verified the.Western Blot detection of PI3K/AKT/m TOR pathway. The phosphorylation level of 0S6K inhibits the activity of the PI3K/AKT/m TOR signaling pathway, but does not have a direct effect on the tumor resistance gene MGMT. After RNA interference silencing ER beta expression, Liq loses its regulatory role in the TOR pathway of PI3K/AKT/m, indicating that Liq is a pathway that regulates the activity of PI3K/AKT/m pathway activity by activating ER beta. The inhibitor XL765 can significantly increase the sensitivity of the cell to TMZ, suggesting that the activation of the PI3K/AKT/m TOR pathway can protect the glioma cells and antagonize the role of TMZ. The combination of PI3K/AKT/m TOR activator IGF-1 can antagonize the toxicity of Liq mediated TMZ, suggesting that Liq is used to inhibit PI3K/AKT/m to play a role. Two, body The results showed that the average volume of tumor in the control group was 1.84 0.13cm3, the average volume of the tumor in the TMZ group was 0.93 + 0.11cm3, the average volume of the tumor in the group Liq was 1.34 + 0.15cm3, and the average volume of the tumor in the group of TMZ and Liq was 0.36 + 0.04cm3., and the results were in accordance with the results of the cell experiment in vitro. The combination of Liq and TMZ was used. It can significantly inhibit tumor growth and increase the sensitivity of tumor to TMZ, and the difference is statistically significant (P0.05). At the same time, Western Blot results show that Liq can increase the expression of ER beta in tumor cells in vivo. It is concluded that Liq may inhibit the growth of tumor by activating ER beta and related signaling pathways in vivo, and improve the sensitivity of tumor cells to TMZ. Inductive effect. Experimental conclusion: 1.Liq can inhibit the proliferation of glioma cell (U138) and obviously promote its apoptosis, which can significantly enhance the sensitivity of tumor cells to TMZ; 2.Liq inhibits the activity of PI3K/AKT/m TOR signaling via specific activation of ER beta; 3.Liq's sensitizing function to TMZ depends on its inhibition of PI3K/AKT/m TOR pathway; 4. in vivo The tumor bearing mice treated with Liq and TMZ found that Liq significantly increased the sensitivity of the tumor cells to TMZ. These results suggest that Liq promotes the effect of TMZ on the treatment of glioma by activating ER beta to inhibit PI3K/AKT/m TOR. The present study also provides other ER beta agonists as an effective chemotherapeutic agent for neuroglioma. Combined treatment provides a basis and clues.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R739.41

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