發(fā)布時(shí)間：2018-08-27 16:52

【摘要】：目的:急性髓系白血病(acute myeloid leukemia,AML)是一類造血干細(xì)胞惡性克隆性疾病,是嚴(yán)重威脅人類健康的疾病。AML主要的治療方法為化療,近年來成人AML患者經(jīng)標(biāo)準(zhǔn)“3+7”化療方案治療后,完全緩解率在70%-80%。同時(shí)由于微小殘留病灶(MRD)的存在,緩解后復(fù)發(fā)是AML病人的危險(xiǎn)因素。只有近20%-30%的AML病人可以獲得無病生存[1]。異基因造血干細(xì)胞移植是治療AML最有效的方法,由于患者客觀條件限制較多(如供著來源、經(jīng)濟(jì)狀況)等多方面的因素,目前能夠接受造血干細(xì)胞移植的AML病人為少數(shù)。因此尋找新的靶向藥物提高化療藥物的效果是我們不斷探索的領(lǐng)域。急性髓系白血病的發(fā)生與細(xì)胞遺傳學(xué)、分子遺傳學(xué)改變有密切關(guān)系,研究發(fā)現(xiàn)大多數(shù)急性髓系白血病(AML)患者中存在2種或2種以上基因異常甲基化,DNA甲基化在白血病中廣泛存在,啟動(dòng)子Cp G島超甲基化導(dǎo)致的抑癌基因失活與白血病的發(fā)生和腫瘤細(xì)胞化療藥物抵抗密切相關(guān)[2]。地西他濱(decitabine,DAC),又稱為5-氮雜-2’-脫氧胞苷,是一種胞嘧啶核苷類似物,為特異的DNA甲基化轉(zhuǎn)移酶抑制劑,是目前研究較多的甲基化抑制劑,可通過逆轉(zhuǎn)Cp G島甲基化,使多種因甲基化而失活的抑癌基因重新表達(dá),抑制腫瘤細(xì)胞生長而達(dá)到治療腫瘤的目的[3]。三氧化二砷(arsenic trioxide,AS2O3)是傳統(tǒng)中藥砒霜的有效成分之一,是治療急性早幼粒細(xì)胞白血病的經(jīng)典藥物之一,該藥物通過誘導(dǎo)白血病細(xì)胞分化及凋亡兩條途徑發(fā)揮其治療作用,隨著對(duì)該藥物的不斷研究,現(xiàn)在逐漸應(yīng)用于其他類型的惡性血液病的治療中[4]。目前去甲基化藥物不斷應(yīng)用于臨床,不僅應(yīng)用于骨髓增生異常綜合征的患者,同時(shí)針對(duì)老年AML、復(fù)發(fā)、難治的AML患者,有一定的效果。研究新的靶向藥物,以提高藥物療效并延長無病生存期是目前研究的重要課題。本實(shí)驗(yàn)研究DAC、AS2O3對(duì)HL-60細(xì)胞(人急性髓系白血病細(xì)胞株)增殖、凋亡的作用以及對(duì)HL-60細(xì)胞端粒酶的基因及蛋白表達(dá)水平變化的的影響,探討去甲基化藥物對(duì)AML的作用機(jī)制,旨在為今后臨床用藥提供更多的理論依據(jù)。方法:選取HL-60(人急性髓系白血病)細(xì)胞株為研究對(duì)象,實(shí)驗(yàn)隨機(jī)分組:設(shè)置未加藥物空白對(duì)照組,單藥DAC組(1μmol/L、10μmol/L、50μmol/L),單藥AS2O3組(1.25μmol/L、2.5μmol/L、5μmol/L)、DAC聯(lián)合AS2O3組(10μmol/L+2.5μmol/L、10μmol/L+5μmol/L、50μmol/L+2.5μmol/L、50μmol/L+5μmol/L),DAC(50μmol/L)預(yù)處理+AS2O3組(1.25μmol/L、2.5μmol/L、5μmol/L)。根據(jù)不同濃藥物度作用HL-60細(xì)胞后,檢測(cè)不同時(shí)間增殖、凋亡的作用以及對(duì)端粒酶基因及蛋白表達(dá)水平的影響。每組實(shí)驗(yàn)重復(fù)3次。1用CCK8法篩查藥物濃度,檢測(cè)不同藥物濃度作用HL-60細(xì)胞24h、48h、72h后的增殖抑制率;2用流式細(xì)胞術(shù)(FCM)檢測(cè)不同藥物濃度作用HL-60細(xì)胞24h、48h、72h后的凋亡率;3用RT-PCR法檢測(cè)不同藥物濃度作用HL-60細(xì)胞48h后端粒酶的h TERT m RNA表達(dá)水平的變化;4用Western Blot法檢測(cè)不同藥物濃度作用HL-60細(xì)胞48h后h TERT的蛋白表達(dá)水平的變化;5用SPSS 21.0統(tǒng)計(jì)軟件進(jìn)行統(tǒng)計(jì)學(xué)處理。所有數(shù)據(jù)用3次獨(dú)立實(shí)驗(yàn)的平均值表示,實(shí)驗(yàn)結(jié)果均采用均數(shù)±標(biāo)準(zhǔn)差(X±S)表示;兩組比較應(yīng)用t檢驗(yàn),多組比較應(yīng)用方差分析,P0.05有統(tǒng)計(jì)學(xué)意義。結(jié)果:1 DAC、AS2O3單藥對(duì)HL-60細(xì)胞株增殖抑制率的檢測(cè)。1.1不同濃度DAC、AS2O3單藥作用于HL-60細(xì)胞24h、48h、72h后,單藥DAC、AS2O3增加藥物濃度和作用時(shí)間延長,可增加增殖抑制率。單藥DAC作用HL-60細(xì)胞后,增殖抑制率由(10.85±2.04)%增加到(56.01±2.04)%,單藥AS2O3作用HL-60細(xì)胞后,增殖抑制率由(14.55±1.68)%增加到(85.09±3.67)%。各藥物處理組之間比較差異有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC、AS2O3單藥均對(duì)HL-60細(xì)胞有抑制增殖的作用,并呈時(shí)間-劑量依賴性。(圖1,圖2,表1,表2)1.2 DAC聯(lián)合AS2O3對(duì)HL-60細(xì)胞作用24h、48h、72h后,不同時(shí)間段兩藥聯(lián)合作用HL-60細(xì)胞,增加藥物聯(lián)合濃度,其增殖抑制率由(35.68±1.98)%增加到(94.89±1.02)%,各聯(lián)合處理組與單藥處理組比較增殖抑制率明顯增高,比較有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC聯(lián)合AS2O3對(duì)HL-60細(xì)胞的抑制作用優(yōu)于單藥。(圖3,表3)1.3經(jīng)DAC(50μmol/L)預(yù)處理后,不同濃度AS2O3對(duì)HL-60細(xì)胞作用24h、48h、72h后,增加藥物濃度和延長作用時(shí)間,可增強(qiáng)增殖抑制率,增殖抑制率由(26.98±0.67)%增加到(93.10±0.80)%,與AS2O3單藥組比較增殖抑制率顯著增加,各藥物處理組間及與AS2O3單藥組之間比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC預(yù)處理可以增強(qiáng)AS2O3對(duì)HL-60細(xì)胞的增殖抑制作用。(圖4,表4)2 DAC、AS2O3單藥對(duì)HL-60細(xì)胞株凋亡的影響2.1單藥DAC、AS2O3作用于HL-60細(xì)胞24h、48h、72h后,凋亡率逐漸升高。單藥DAC對(duì)HL-60細(xì)胞凋亡率由(7.61±1.02)%增加到(36.33±0.51)%,單藥AS2O3對(duì)HL-60細(xì)胞凋亡率由(9.80±0.26)%增加到(40.56±0.90)%。各藥物處理組間以及與空白對(duì)照組之間比較差異有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC、AS2O3單藥能夠誘導(dǎo)HL-60細(xì)胞凋亡,并呈時(shí)間-劑量依賴性。(圖5,表5,表6)2.2 DAC聯(lián)合AS2O3對(duì)HL-60細(xì)胞作用24h、48h、72h后,凋亡率由(18.00±1.37)%增加到(57.76±0.61)%,各聯(lián)合組與單藥組比較凋亡率顯著增加,且差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC聯(lián)合AS2O3對(duì)HL-60細(xì)胞誘導(dǎo)凋亡具有協(xié)同作用。(圖5,表7)2.3經(jīng)DAC(50μmol/L)預(yù)處理后,不同濃度的AS2O3對(duì)HL-60細(xì)胞作用24h、48h、72h后,凋亡率隨藥物濃度的增加和作用時(shí)間的延長而增加,凋亡率由(17.93±0.55)%增加到(60.96±0.70)%,較AS2O3單藥組凋亡率明顯增加。各AS2O3濃度經(jīng)DAC預(yù)處理后與AS2O3單藥組比較差異有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC預(yù)處理可以增強(qiáng)AS2O3對(duì)HL-60細(xì)胞誘導(dǎo)凋亡的作用。(圖5,表8)3 DAC、AS2O3對(duì)HL-60細(xì)胞內(nèi)端粒酶h TERT m RNA表達(dá)水平變化的影響3.1不同濃度DAC、AS2O3單藥對(duì)HL-60細(xì)胞作用48h后,增加藥物濃度,端粒酶h TERT m RNA表達(dá)水平有下降。單藥DAC(0μmol/L、1μmol/L、10μmol/L、50μmol/L),對(duì)h TERT m RNA的表達(dá)量由0.993±0.007下降到0.578±0.004;單藥AS2O3(0μmol/L、1.25μmol/L、2.5μmol/L、5μmol/L)對(duì)h TERT m RNA的表達(dá)量由0.993±0.007下降到0.657±0.034。各處理組間h TERT m RNA比較,差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC、AS2O3單藥能夠降低HL-60細(xì)胞內(nèi)端粒酶h TERT m RNA基因的表達(dá)水平,呈劑量依賴性。(圖6,表9,表10)3.2不同濃度的DAC聯(lián)合AS2O3對(duì)HL-60細(xì)胞作用48h后,增加聯(lián)合組藥物濃度,對(duì)h TERT m RNA的表達(dá)量由0.528±0.022下降到0.213±0.023。各處理組之間h TERT m RNA表達(dá)水平差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC聯(lián)合AS2O3能夠增加HL-60細(xì)胞內(nèi)端粒酶h TERT m RNA的表達(dá)水平,且兩者具有協(xié)同作用。(圖6,表11)3.3經(jīng)DAC(50μmol/L)預(yù)處理后,不同藥物濃度的AS2O3對(duì)HL-60細(xì)胞作用48h后,增加藥物濃度,h TERT m RNA的表達(dá)量由0.161±0.022下降到0.065±0.008,較AS2O3單藥組比較表達(dá)水平顯著下降,h TERT m RNA各處理組間及與單藥AS2O3比較h TERT m RNA差異均具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC預(yù)處理可以增加AS2O3對(duì)HL-60細(xì)胞內(nèi)端粒酶h TERT m RNA的抑制作用。(圖6,表12)4 DAC、AS2O3對(duì)HL-60細(xì)胞端粒酶內(nèi)h TERT蛋白表達(dá)水平變化的影響4.1不同濃度DAC、AS2O3單藥對(duì)HL-60細(xì)胞作用48h后,隨著藥物濃度的增加,端粒酶h TERT的蛋白表達(dá)水平有下降。單藥DAC(0μmol/L、1μmol/L、10μmol/L、50μmol/L)對(duì)h TERT的蛋白相對(duì)表達(dá)量由1.046±0.073下降到0.576±0.063;單藥AS2O3(0μmol/L、1.25μmol/L、2.5μmol/L、5μmol/L)對(duì)h TERT的蛋白相對(duì)表達(dá)量由1.046±0.073下降到0.426±0.014。各處理組間及處理組與空白對(duì)照組之間比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC、AS2O3單藥能夠降低HL-60細(xì)胞內(nèi)端粒酶h TERT蛋白的表達(dá),并呈劑量依賴性。(圖7,表13,表14)4.2不同濃度的DAC聯(lián)合AS2O3對(duì)HL-60細(xì)胞作用48h后,隨著藥物濃度的增加,對(duì)h TERT的蛋白相對(duì)表達(dá)量由0.674±0.016下降到0.111±0.015,且差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC聯(lián)合AS2O3能夠抑制HL-60細(xì)胞端粒酶h TERT蛋白的表達(dá),且兩者具有協(xié)同作用。(圖8,表15)4.3經(jīng)DAC(50μmol/L)預(yù)處理后,不同藥物濃度的AS2O3對(duì)HL-60細(xì)胞作用48h后,增加藥物濃度,端粒酶的h TERT的蛋白相對(duì)表達(dá)量由0.311±0.015下降到0.055±0.011,較AS2O3單藥組蛋白相對(duì)表達(dá)量顯著下降,各藥物處理組間及各處理組與AS2O3單藥組間比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.00)。說明DAC預(yù)處理可以提升AS2O3對(duì)HL-60細(xì)胞端粒酶h TERT蛋白的抑制作用。(圖9,表16)結(jié)論:1不同濃度地西他濱和三氧化二砷及兩藥聯(lián)合作用HL-60細(xì)胞株后,均有抑制增殖、誘導(dǎo)凋亡的作用,并呈劑量-時(shí)間依賴性。2地西他濱和三氧化二砷發(fā)揮作用具有協(xié)同效應(yīng)。3經(jīng)地西他濱預(yù)處理后,可以增加三氧化二砷對(duì)HL-60細(xì)胞株的敏感性,其作用機(jī)制可能與降低端粒酶h TERT的表達(dá)有關(guān),端粒酶h TERT可能是DAC誘導(dǎo)HL-60細(xì)胞凋亡的調(diào)控基因之一。
[Abstract]:Objective: Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem cells and a serious threat to human health. Chemotherapy is the main treatment for AML. In recent years, the complete remission rate of adult AML patients is 70% - 80% after the standard "3 + 7" chemotherapy regimen. Alien hematopoietic stem cell transplantation is the most effective method to treat AML. Due to the limited objective conditions (such as source of supply, economic status) and other factors, it is now possible to accept hematopoietic stem cell transplantation. The incidence of acute myeloid leukemia is closely related to cytogenetics and molecular genetics. It has been found that there are two or more abnormal gene methylation, DN in most patients with acute myeloid leukemia (AML). A-methylation is widespread in leukemia, and the inactivation of tumor suppressor genes caused by hypermethylation of promoter Cp G islands is closely related to the occurrence of leukemia and the resistance of tumor cells to chemotherapeutic drugs [2].Decitabine (DAC), also known as 5-aza-2'-deoxycytidine, is a cytosine nucleoside analogue that inhibits specific DNA methylation transferase Preparations, as methylation inhibitors, have been extensively studied. They can reverse the methylation of Cp G islands, re-express many tumor suppressor genes inactivated by methylation, inhibit the growth of tumor cells and achieve the purpose of tumor treatment [3]. Arsenic trioxide (AS2O3) is one of the effective components of traditional Chinese medicine arsenic, and is an early treatment for acute diseases. Meiocytic leukemia is one of the classical drugs. It plays a therapeutic role by inducing differentiation and apoptosis of leukemic cells. With the continuous study of this drug, it is gradually used in the treatment of other types of malignant hematological diseases [4]. It is an important subject to study new targeted drugs to improve the efficacy of drugs and prolong disease-free survival. In this study, the effects of DAC and AS2O3 on proliferation, apoptosis and apoptosis of HL-60 cells (human acute myeloid leukemia cell line) were studied. To investigate the effect of demethylation drugs on the expression of telomerase gene and protein in HL-60 cells, and to explore the mechanism of demethylation drugs on AML, so as to provide more theoretical basis for clinical use in the future. DAC group (1 micromolmolmol/L, 10 micromolmol/L, 10 micromol/L, 50 micromolmolmolmolmol/L, 50 micromolmolmolmol/L), single drug AS2O3 group (1.25 micromolmol/L, 2.5 micromolmol/L, 5 micromolmolmolmol/L, 5 micromolmol/L), DAC combined with AS2O3 group (10 micromolmol/L+2.5 micromol/L, 10 micromolmolmolmolmol/L, 10 micromolmolmol/L/L, 10 10 micromolmolmolmolmolmolmolmolmolmol/L/L, 10 10 micromolmolmolmolmolmolmolmolmolmolL/L/L/L 10 10 10 0/L, 10 micromolmolmolmolmolmolmolmolmolmolmolmolmolL/L/L 10 10 0/L 10(2) After HL-60 cells were treated with different concentrations of the drug, The proliferation and apoptosis of HL-60 cells at different time and the expression of telomerase gene and protein were detected. The apoptotic rate of HL-60 cells was measured by RT-PCR. The expression of H TERT m RNA was detected by RT-PCR. The expression of H TERT m RNA was detected by Western Blot. The expression of H TERT protein was analyzed by SPSS 21.0 software. Results: 1 DAC, AS2O3 single drug inhibited the proliferation of HL-60 cells. 1.1 Different concentrations of DAC, AS2O3 single drug acted on HL-60 cells 24 hours, 48 hours, 72 hours, single drug DAC, A The inhibitory rate of proliferation of HL-60 cells treated with single drug DAC increased from (10.85 [2.04]% to (56.01 [2.04])%. The inhibitory rate of proliferation of HL-60 cells treated with single drug AS2O3 increased from (14.55 [1.68]% to (85.09 [3.67]%). There was a significant difference between the treatment groups (P The results showed that DAC and AS2O3 could inhibit the proliferation of HL-60 cells in a time-and dose-dependent manner. (Fig. 1, 2, 1, 2) 1.2 DAC combined with AS2O3 could inhibit the proliferation of HL-60 cells for 24, 48 and 72 hours, and the inhibitory rate increased from (35.68 (1.98)% to (94.89 (1.02)) The inhibitory effect of DAC combined with AS2O3 on HL-60 cells was superior to that of single drug (P = 0.00). (Fig. 3, Table 3) After pretreatment with DAC (50 micromol/L), AS2O3 at different concentrations increased the inhibitory effect on HL-60 cells for 24 hours, 48 hours and 72 hours. The inhibition rate of proliferation increased from (26.98 (Fig. 4, Table 4) 2 DAC, AS2O3 monotherapy on apoptosis of HL-60 cell line 2.1 single drug DAC, AS2O3 on HL-60 cell 24 hours, 48 hours, 72 hours, the apoptosis rate gradually increased. Single drug DAC on HL-60 cell apoptosis rate increased from (7.61 [1.02]% to (36.33 [0.51)%]%, single drug AS2O3 on HL-60 cell apoptosis rate increased from (9.80 [0.26]% to (40.56 [0.90)%]. The results showed that DAC and AS2O3 could induce apoptosis of HL-60 cells in a time-and dose-dependent manner. (Fig. 5, Table 5, Table 6) 2.2 DAC combined with AS2O3 could induce apoptosis of HL-60 cells 24 hours, 48 hours and 72 hours later, the apoptosis rate increased from (18.00 (1.37)% to (57.76 (0.61)% in each combination group compared with the single drug group. The apoptosis rate of HL-60 cells was significantly higher than that of HL-60 cells, and the difference was statistically significant (P=0.00). It showed that DAC combined with AS2O3 had synergistic effect on HL-60 cells. (Fig. 5, Table 7) After pretreatment with DAC (50 micromol/L), the apoptosis rate of HL-60 cells treated with different concentrations of AS2O3 for 24 hours, 48 hours, 72 hours increased with the increase of drug concentration and prolonged action time, and withered. The apoptosis rate of HL-60 cells increased from (17.93 6550 Effects of different concentrations of DAC, AS2O3 monotherapy on HL-60 cells 48 hours after treatment, increased drug concentration, telomerase h TERT m RNA expression level decreased. Single drug DAC (0 micromol/L, 1 micromol/L, 10 micromol/L, 50 micromol/L), the expression of H TERT m RNA decreased from 0.993 (+0.007) to 0.578 (+0.004); single drug AS2O3 (0 micromol/L, 1.25 micromol/L, 2.25 micromol/L). The expression of H TERT m RNA in HL-60 cells was decreased from 0.993.007 to 0.657.034 by 5 The expression of H TERT m RNA in HL-60 cells decreased from 0.528 (+0.022) to 0.213 (+0.023) 48 hours after the combination of DAC and AS2O3. There was a significant difference in the expression level of H TERT m RNA between the treatment groups (P = 0.00). It indicated that DAC combined with AS2O3 could increase the expression level of H TERT m RNA in HL-60 cells, and the expression level of H TERT m RNA in both groups was increased. After pretreatment with DAC (50 micromol/L), the expression of H TERT-m RNA decreased from 0.161 (+ 0.022) to 0.065 (+ 0.008) after 48 hours of treatment with different concentrations of AS2O3, which was significantly lower than that of AS2O3 alone. The expression of H TERT-m RNA was significantly lower in each treatment group and compared with that of AS2O3 alone. The difference of TERT m RNA was statistically significant (P = 0.00). It indicated that DAC pretreatment could increase the inhibitory effect of AS2O3 on telomerase h TERT m RNA in HL-60 cells. (Fig. 6, Table 12) 4 DAC, AS2O3 on the expression of H TERT protein in HL-60 cells 4. The relative expression of H TERT protein decreased from 1.046.073 to 0.576.063 in DAC (065 The results showed that DAC and AS2O3 could decrease the expression of telomerase h TERT protein in HL-60 cells in a dose-dependent manner. (Fig. 7, Table 13, Table 14)4.2 Different concentrations of DAC combined with AS2O3 could increase the concentration of DAC in HL-60 cells 48 hours after treatment. The relative expression of H TERT protein decreased from 0.674 [0.016] to 0.111 [0.015], and the difference was statistically significant (P = 0.00). It indicated that DAC combined with AS2O3 could inhibit the expression of H TERT protein in HL-60 cells, and the two had synergistic effects. (Fig. 8, Table 15) After pretreatment with DAC (50 um mol/L), AS2O3 at different concentrations acted on HL-60 cells. After 48 hours of treatment, the relative expression of H TERT protein of telomerase decreased from 0.311 (+ 0.015) to 0.055 (+ 0.011), which was significantly lower than that of AS2O3. There was a significant difference between the treatment groups and the AS2O3 group (P = 0.00). Inhibitory effect of H TERT protein on telomerase activity in HL-60 cells. (Fig. 9, Table 16) Conclusion: 1 Different concentrations of dicitabine, arsenic trioxide and their combination can inhibit proliferation and induce apoptosis of HL-60 cells in a dose-time dependent manner. After treatment, arsenic trioxide can increase the sensitivity of HL-60 cells. The mechanism may be related to the decrease of telomerase h TERT expression. Telomerase h TERT may be one of the regulatory genes of DAC-induced apoptosis of HL-60 cells.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R733.71

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