本文選題：褪黑素 + 5-FU��； 參考：《大連醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:結(jié)腸癌在全球范圍內(nèi)其死亡率高居第三位。5-FU在結(jié)腸癌治療中是最常用的化療藥物之一,但是由于其本身的致毒性導(dǎo)致其治療指數(shù)的局限性。褪黑素已被證實具有抗腫瘤活性并且可與其他化學(xué)治療藥聯(lián)合用于癌癥治療。然而,尚未報道褪黑素與5-FU聯(lián)合用藥治療結(jié)腸癌能否提高5-FU的治療療效。我們的研究目的是為了探究這樣一種聯(lián)合用藥褪黑素是否可協(xié)同提高5-FU抑制結(jié)腸癌細胞增殖和促進凋亡作用。方法:本研究中,單獨褪黑素、單獨5-FU和褪黑素聯(lián)合5-FU處理人結(jié)腸癌細胞SW620和LOVO,MTT法檢測細胞活力,通過克隆形成實驗、劃痕實驗、侵襲實驗、凋亡和周期實驗檢測不同藥物處理的細胞生物學(xué)功能。在分子機制研究中,Western blot檢測PI3K/AKT/NF-κB/iNOS信號通路的一些關(guān)鍵蛋白。進一步通過不同藥物處理組進行激光共聚焦掃描顯微鏡和染色質(zhì)免疫共沉淀實驗研究NF-κB p50/p65的核定位及它們與iNOS的啟動子區(qū)的結(jié)合情況。最后,利用荷瘤小鼠實驗,研究褪黑素協(xié)同增強5-FU的抗腫瘤活性。結(jié)果:與單獨5-FU藥物處理組相比,聯(lián)合褪黑素與5-FU藥物處理組能夠顯著抑制結(jié)腸癌細胞增殖、克隆形成、細胞遷移及侵襲并能夠顯著改變細胞的形態(tài)。除此之外,聯(lián)合褪黑素和5-FU藥物處理組能夠更明顯的誘導(dǎo)結(jié)腸癌細胞周期阻滯和激活細胞凋亡蛋白酶依賴的凋亡通路。進一步的分子機制實驗表明這樣一種聯(lián)合用藥與單獨5-FU藥物處理更能顯著抑制PI3K/AKT和NF-κB/iNOS信號通路的激活。褪黑素協(xié)同加強5-FU抑制PI3K或iNOS的活性。更重要的是,與單獨5-FU藥物處理組相比,聯(lián)合褪黑素的5-FU藥物處理組更加顯著地抑制了荷瘤小鼠模型體內(nèi)的結(jié)腸癌的生長,同樣地更加明顯抑制了AKT和iNOS的活性。結(jié)論:本研究發(fā)現(xiàn)與單獨5-FU藥物處理組相比,聯(lián)合褪黑素的5-FU藥物處理組能夠顯著提高抑制結(jié)腸癌生長作用。更重要的是,研究表明這樣一種在結(jié)腸癌中抗增殖和促凋亡的作用提高是通過調(diào)節(jié)多個信號通路包括PI3K/AKT和NF-κB/iNOS。
[Abstract]:Objective: colon cancer is one of the most commonly used chemotherapeutic drugs in colon cancer treatment, but its treatment index is limited due to its toxicity. Melatonin has been proven to have anti-tumor activity and can be used in combination with other chemotherapeutic drugs for cancer treatment. However, whether the combination of melatonin and 5-FU can improve the efficacy of 5-FU in colon cancer has not been reported. Our aim was to investigate whether melatonin, a combination of these drugs, can increase the proliferation and apoptosis of colon cancer cells in combination with 5-FU. Methods: in this study, single melatonin, 5-FU and 5-FU combined with 5-FU were used to detect the viability of human colon cancer cell line SW620 and LOVOA MTT. Apoptosis and periodic experiments were used to detect the biological function of different drugs. Some key proteins in the PI3K / AKT / NF- 魏 B / iNOS signaling pathway were detected by Western blot. Furthermore, laser confocal scanning microscopy and chromatin immunoprecipitation were used to study the nuclear localization of NF- 魏 B p50/p65 and the binding of NF- 魏 B p50/p65 to the promoter region of iNOS. Finally, the anti-tumor activity of 5-Fu was studied by using melatonin in tumor-bearing mice. Results: the combination of melatonin and 5-FU could significantly inhibit the proliferation, clone formation, cell migration and invasion of colon cancer cells and significantly change the morphology of colon cancer cells. In addition, the combination of melatonin and 5-FU could induce cell cycle arrest and activation of apoptotic protease-dependent apoptosis pathway in colon cancer cells. Further molecular mechanism experiments showed that the combination of 5-FU and 5-FU could significantly inhibit the activation of PI3K / AKT and NF- 魏 B / iNOS signaling pathway. Melatonin synergistically inhibits the activity of PI3K or iNOS by 5-FU. More importantly, 5-FU combined with melatonin significantly inhibited the growth of colon cancer and the activity of AKT and iNOS in tumor-bearing mice compared with 5-FU alone. Conclusion: compared with 5-FU alone, 5-FU combined with melatonin can significantly inhibit the growth of colon cancer. More importantly, studies have shown that such an anti-proliferation and pro-apoptotic role in colon cancer is enhanced by regulating multiple signaling pathways, including PI3K / AKT and NF- 魏 B / iNOS.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.35

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本文編號：2090242