本文關(guān)鍵詞： 粉防己堿 三氧化二砷 乳腺癌肺轉(zhuǎn)移 HCC1937 MDA-MB-435S　出處：《北京中醫(yī)藥大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：研究目的：本課題在既往研究基礎(chǔ)上,分析粉防己堿、三氧化二砷及兩藥聯(lián)合對(duì)MDA-MB-435S細(xì)胞和HCC1937細(xì)胞體外的抑制增殖作用及促凋亡機(jī)制。體內(nèi)實(shí)驗(yàn)則利用MDA-MB-435S細(xì)胞接種的裸鼠乳腺癌肺轉(zhuǎn)移模型來(lái)觀察粉防己堿、三氧化二砷及兩藥聯(lián)合與化療藥順鉑的抑瘤作用及其與腫瘤血管生成相關(guān)指標(biāo)的表達(dá),同時(shí)檢測(cè)各組裸鼠肝腎功能以判斷毒性中藥安全性。以期為中醫(yī)“以毒攻毒”指導(dǎo)下的中藥配伍組合治療乳腺癌及乳腺癌肺轉(zhuǎn)移提供相關(guān)實(shí)驗(yàn)依據(jù)。研究方法：體外實(shí)驗(yàn)利用MTT方法檢測(cè)經(jīng)不同濃度粉防己堿、三氧化二砷及粉防己堿聯(lián)合三氧化二砷對(duì)MDA-MB-435S及HCC1937乳腺癌細(xì)胞在不同時(shí)間點(diǎn)(24、48、72、96h)的抑制作用及藥物濃度與時(shí)間關(guān)系。利用中效原理(Chou-Talalay合用指數(shù)法)判斷聯(lián)合用藥效果最好的藥物配比以指導(dǎo)后續(xù)實(shí)驗(yàn)。采用倒置相差熒光顯微鏡觀察不同濃度粉防己堿、三氧化二砷及兩藥聯(lián)合干預(yù)48小時(shí)后MDA-MB-435S及HCC1937乳腺癌細(xì)胞的形態(tài)學(xué)變化,探究藥物的作用效果。采用AnnexinV-FITC、PI雙染流式細(xì)胞術(shù)測(cè)定不同濃度粉防己堿、三氧化二砷及兩藥聯(lián)合干預(yù)48小時(shí)后MDA-MB-435S及HCC1937乳腺癌細(xì)胞早期凋亡、晚期凋亡的比例變化,探究?jī)伤帉?duì)腫瘤細(xì)胞凋亡影響。采用腫瘤侵襲實(shí)驗(yàn)檢測(cè)不同濃度粉防己堿、三氧化二砷及兩藥聯(lián)合干預(yù)48小時(shí)后MDA-MB-435S及HCC1937乳腺癌細(xì)胞的侵襲能力是否受到藥物抑制及其抑制程度。采用RT-PCR及Western blot方法分析粉防己堿聯(lián)合三氧化二砷干預(yù)48小時(shí)后MDA-MB-435S及HCC1937乳腺癌細(xì)胞凋亡相關(guān)基因蛋白Caspase-3、PARP、Bid、 Bax、Bcl-2、survivin、AKT的表達(dá)及相關(guān)作用機(jī)制。體內(nèi)試驗(yàn)采用高肺轉(zhuǎn)移率人乳腺癌細(xì)胞MDA-MB-435S種植于BALB/c裸鼠乳房墊下以形成乳腺癌肺轉(zhuǎn)移模型,造模成功后采用漢防己甲素注射液、亞砷酸注射液、順鉑注射液及漢防己甲素注射液聯(lián)合亞砷酸注射液觀察裸鼠一般生存情況、抑瘤率、肺轉(zhuǎn)移率、肝腎功能等指標(biāo),對(duì)瘤體及肺組織做HE染色切片,免疫組化、RT-PCR及Westernblot觀察VEGF、MMPs等血管生成相關(guān)基因、蛋白表達(dá)情況,說(shuō)明其作用通路。研究結(jié)果：體外實(shí)驗(yàn)中發(fā)現(xiàn)粉防己堿、三氧化二砷及粉防己堿聯(lián)合三氧化二砷對(duì)MDA-MB-435S及HCC1937乳腺癌細(xì)胞的體外生長(zhǎng)均有較為顯著的抑制效果,與藥物劑量、作用時(shí)間呈明顯關(guān)系,抑制率隨作用時(shí)間的延長(zhǎng)及藥物濃度增加上升,且時(shí)間與藥物劑量間存在交互效應(yīng)。根據(jù)中效原理(Chou-Talalay合用指數(shù)法)及calcusyn2.0軟件得出兩藥聯(lián)合作用于MDA-MB-435S及HCC1937乳腺癌細(xì)胞,在粉防己堿(1μg/mL)和三氧化二砷(1.5μg/mL)時(shí)協(xié)同作用最好,遂選取該組合作為后期實(shí)驗(yàn)選取的合藥濃度。細(xì)胞形態(tài)學(xué)研究顯示,粉防己堿、三氧化二砷及粉防己堿聯(lián)合三氧化二砷均可使細(xì)胞形態(tài)發(fā)生改變且與藥物劑量大小有關(guān),且合藥效果優(yōu)于單藥。細(xì)胞大量死亡、崩解,貼壁數(shù)量顯著減少。流式細(xì)胞術(shù)雙染檢測(cè)凋亡可發(fā)現(xiàn)粉防己堿、三氧化二砷及兩藥聯(lián)合干預(yù)MDA-MB-435S及HCC1937乳腺癌細(xì)胞48h小時(shí)早期凋亡率和晚期凋亡率均有上升,且合藥較之單藥細(xì)胞凋亡率增加。腫瘤侵襲實(shí)驗(yàn)發(fā)現(xiàn)在粉防己堿、三氧化二砷干預(yù)MDA-MB-435S及HCC1937乳腺癌細(xì)胞48小時(shí)后,穿膜進(jìn)入下室的細(xì)胞數(shù)具有差異,且藥物濃度越大穿膜細(xì)胞數(shù)越少。兩藥聯(lián)合作用效果較之同濃度單藥并無(wú)明顯差異。通過(guò)RT-PCR對(duì)凋亡相關(guān)基因表達(dá)情況進(jìn)行分析發(fā)現(xiàn)：經(jīng)粉防己堿聯(lián)合三氧化二砷干預(yù)48小時(shí)后,MDA-MB-435S及HCC1937細(xì)胞中Caspase-3、bax、bid相關(guān)基因表達(dá)隨藥物濃度變化升高,Bcl-2、suivivin調(diào)控基因的表達(dá)降低。且粉防己堿與三氧化二砷聯(lián)合用藥效果,優(yōu)于等濃度的單一用藥效果。Western bolt實(shí)驗(yàn)發(fā)現(xiàn),MDA-MB-435S及HCC1937細(xì)胞經(jīng)藥物作用后Caspase 3前體表達(dá)量減少,反之切割體表達(dá)量增加。下游PRAP的酶切條帶提示細(xì)胞凋亡的發(fā)生。Bcl-2表達(dá)降低,Bax、Bid表達(dá)增加,且合藥作用優(yōu)于等濃度單藥。Survivin的表達(dá)在兩藥單獨(dú)作用時(shí)與空白組無(wú)明顯差異,合藥則在該蛋白的表達(dá)上降低明顯。體內(nèi)試驗(yàn)表明漢防己甲素注射液、亞砷酸注射液及兩藥聯(lián)合均可減慢腫瘤生長(zhǎng),抑制肺轉(zhuǎn)移發(fā)生,但較之順鉑則效果略差。兩藥單用及合用均對(duì)裸鼠肝腎功能無(wú)明顯損害。對(duì)裸鼠瘤體及肺組織進(jìn)行采用RT-PCR及Western blot檢測(cè)發(fā)現(xiàn),漢防己甲素注射液、亞砷酸注射液及兩藥聯(lián)合均可降低VEGF表達(dá),且合藥組比單藥組表達(dá)更低。研究結(jié)論：粉防己堿、三氧化二砷及兩藥聯(lián)合在體外MDA-MB-435S及HCC1937細(xì)胞增殖有明顯抑制作用,且與藥物劑量及作用時(shí)間相關(guān)性強(qiáng)。在粉防己堿(1μg/mL)和三氧化二砷(1.5μg/mL)時(shí)協(xié)同作用最好。不同濃度粉防己堿、三氧化二砷及兩藥聯(lián)合干預(yù)48h后,MDA-MB-435S及HCC1937細(xì)胞在早期凋亡率和晚期凋亡率均有所提高,侵襲功能減弱。通過(guò)降低Bcl-2,升高Bax、 Bid表達(dá),影響Caspase-3來(lái)誘導(dǎo)乳腺癌細(xì)胞的體外凋亡體內(nèi)實(shí)驗(yàn)表明MDA-MB-435S細(xì)胞接種的裸鼠乳腺癌模型造模成功,肺轉(zhuǎn)移率高,漢防己甲素注射液、亞砷酸注射液及兩藥聯(lián)合均可抑制瘤體生長(zhǎng)及肺轉(zhuǎn)移發(fā)生。其作用機(jī)制與降低VEGF表達(dá),影響腫瘤血管生成有關(guān)。
[Abstract]:Objective: in this study, based on previous study, analysis of tetrandrine, arsenic trioxide and the combination of the two drugs in vitro MDA-MB-435S cells and HCC1937 cell proliferation inhibition and apoptosis mechanism. In vivo experiments using MDA-MB-435S cells in nude mice inoculated with breast cancer lung metastasis model to observe the effect of tetrandrine on the expression of tumor related indicators, the effect of arsenic trioxide and the two drugs combined with cisplatin and tumor angiogenesis, and to detect the nude mice liver and kidney function to determine the toxicity of traditional Chinese medicine safety. In order to "fight" under the guidance of the traditional Chinese medicine combination compatibility of traditional Chinese medicine treatment of breast cancer and pulmonary metastasis of breast cancer to provide experimental basis. Methods: in vitro were detected by MTT. With different concentrations of tetrandrine, arsenic trioxide and tetrandrine combined with arsenic trioxide on MDA-MB-435S and HCC1937 in breast cancer cells At different time points (24,48,72,96h) and the inhibitory effect of the drug concentration and time. The median effect principle (Chou-Talalay share index) to determine the effect of drug combination the best drug ratio in order to guide the subsequent experiment. Using the inverted fluorescence microscope observation of different concentrations of tetrandrine, morphological changes of MDA-MB-435S and HCC1937 in breast cancer cells after 48 hours the joint intervention of arsenic trioxide and explore the effect of two drugs drugs. Using AnnexinV-FITC, PI double staining were measured at different concentrations of tetrandrine in flow cytometry, arsenic trioxide and two drug combination intervention after 48 hours of MDA-MB-435S and HCC1937 in breast cancer cells early apoptosis, late apoptosis ratio changes, explore the impact of the two drugs on the apoptosis of tumor cells. The tumor invasion assay with different concentrations of tetrandrine, HCC1937 and MDA-MB-435S after 48 hours and two drug intervention combined with arsenic trioxide Breast cancer cell invasion and the degree of inhibition by whether the drug inhibition by RT-PCR and Western. Blot analysis of tetrandrine combined with arsenic trioxide and apoptosis of MDA-MB-435S breast cancer cell HCC1937 gene protein Caspase-3, after 48 hours of treatment PARP, Bid, Bax, Bcl-2, survivin, AKT expression and mechanism in vivo by high. The rate of lung metastasis of human breast cancer cells grown in MDA-MB-435S BALB/c nude mice breast pad to form a model of pulmonary metastasis of breast cancer, after the success of modeling by Tetrandrine Hydrochloride Injection, Cisplatin Injection and Tetrandrine Hydrochloride Injection arsenious acid injection combined with Arsenious Acid Injection were observed general survival, tumor inhibition rate, the rate of lung metastasis, liver and kidney function and other indicators, do HE staining the tumor and lung tissue, immunohistochemistry, RT-PCR and Westernblot were VEGF, MMPs and other angiogenesis related genes, eggs White expression, indicating its pathway. Results: it was found that tetrandrine in vitro growth inhibitory effect was more significant in vitro arsenic trioxide and tetrandrine combined with arsenic trioxide on MDA-MB-435S and HCC1937 in breast cancer cells, and the drug dose, as time was, the inhibition rate with the increase of the incubation time and drug the concentration increased, and the time and dose effect. According to the interaction between the efficiency principle (Chou-Talalay combination index method) and calcusyn2.0 software to get the combined effects of two drugs on MDA-MB-435S and HCC1937 in breast cancer cells, tetrandrine (1 g/mL) and arsenic trioxide (1.5 g/mL) when the best synergism, and concentration then select the combination as a late experiment. Cell morphology showed that tetrandrine, arsenic trioxide and tetrandrine combined with three oxidation two arsenic can cause cell Changing the shape and size of the dose related and drug effect is better than the single drug. A large number of cell death, disintegration, the adherent population decreased significantly. Double staining of apoptosis can be found in tetrandrine flow cytometry combined intervention of arsenic trioxide and two drugs MDA-MB-435S and HCC1937 breast cancer cells 48h hours apoptotic rate the rate increased, compared with single drug and drug cell apoptosis rate increased. Tumor invasion was found in tetrandrine, arsenic trioxide intervention MDA-MB-435S and HCC1937 breast cancer cells 48 hours after penetrating the lower chamber of the number of cells with different drug concentration, and larger transmembrane cell number less. Significant difference between the two the medicine combined effect compared with the same concentration. There is no single drug case analysis found by RT-PCR on the expression of apoptosis related genes by tetrandrine combined with arsenic trioxide 48 hours after intervention, MDA-MB-435S and HCC Caspase-3, 1937 in Bax cells, bid gene expression changes with the concentration of drug increased Bcl-2, reduce the expression of suivivin gene. And the effects of tetrandrine combined with arsenic trioxide treatment effect, found that the effect of.Western bolt experiment is better than single drug concentration, MDA-MB-435S and HCC1937 cells after drug action Caspase expression before 3 to reduce the amount of instead of cutting body weight increases. The expression of downstream PRAP enzyme bands indicated that cell apoptosis decreased expression of.Bcl-2, Bax, Bid expression increased, expression and drug effect is better than the single drug concentration of.Survivin in the two drug alone and blank group had no significant difference, and medicine in the expression of the protein on the lower in vivo tests show obvious. Tetrandrine Hydrochloride Injection, combined with Arsenious Acid Injection and two drugs can slow tumor growth, inhibit the occurrence and metastasis to the lungs, but the effect is slightly worse than cisplatin two drugs used. And combined liver and kidney function of nude mice without obvious damage. The body and lung tissue of nude mice tumor were performed by RT-PCR and Western blot detection, Tetrandrine Hydrochloride Injection, combined with Arsenious Acid Injection and two drugs can reduce the expression of VEGF, and the combined drug group expressed lower than the single drug group. Conclusions: tetrandrine, arsenic trioxide and two drugs United has obvious inhibitory effect on the proliferation of the MDA-MB-435S cells and HCC1937 cells, and the drug dose and action time. The strong correlation between tetrandrine (1 g/mL) and arsenic trioxide (1.5 g/mL) at different concentration. The best synergistic effect of tetrandrine combined intervention of arsenic trioxide and two 48h after the administration of MDA-MB-435S and HCC1937 cells the increase in the early and late apoptosis rate were decreased. Invasion function by decreasing Bcl-2, increasing Bax, Bid expression in vitro apoptosis in vivo to induce breast cancer cells Caspase-3 Experiments show that the nude mice model of breast cancer MDA-MB-435S cell vaccination model was successful, lung metastasis rate is high, Tetrandrine Hydrochloride Injection, combined with Arsenious Acid Injection and two drugs can inhibit the growth and metastasis of lung tumor. The mechanism is related to the decreased expression of VEGF, tumor angiogenesis.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R273

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