本文選題：隱丹參酮 + 胃癌�。� 參考：《黑龍江八一農(nóng)墾大學(xué)》2017年碩士論文

【摘要】：目的:胃癌是常見(jiàn)的消化系統(tǒng)惡性腫瘤之一。在我國(guó),因胃癌死亡的人數(shù)遠(yuǎn)高于世界平均水平,嚴(yán)重威脅人們的健康及生命。因此,尋找一種高效、安全、價(jià)格低廉的抗癌藥物勢(shì)在必行。隱丹參酮是由唇形科植物丹參的干燥根和根莖中提取出來(lái)化合物單體,具有抗菌、抗炎及抗癌等多種藥理作用,但其具體的分子藥理機(jī)制尚不清楚。隱丹參酮具有抗腫瘤活性,并已經(jīng)在肺癌及前列腺癌細(xì)胞中得到證實(shí)。本研究利用異種移植瘤裸鼠模型和胃癌細(xì)胞系,從動(dòng)物、細(xì)胞及分子水平上,闡明了隱丹參酮對(duì)胃癌細(xì)胞的殺傷作用、阻滯細(xì)胞周期作用、誘導(dǎo)凋亡作用及相關(guān)信號(hào)轉(zhuǎn)導(dǎo)途徑,為臨床治療胃癌提供一定的理論依據(jù)。方法:本論文利用噻唑藍(lán)比色法檢測(cè)細(xì)胞存活率;利用Annexin V/PI雙染法、流式細(xì)胞術(shù)及蛋白質(zhì)免疫印跡法檢測(cè)細(xì)胞凋亡情況;利用流式細(xì)胞術(shù)和蛋白質(zhì)免疫印跡法檢測(cè)細(xì)胞周期阻滯情況;利用蛋白質(zhì)免疫印跡法檢測(cè)細(xì)胞內(nèi)MAPK、AKT及STAT3信號(hào)通路相關(guān)蛋白的表達(dá)情況;利用流式細(xì)胞術(shù)和蛋白質(zhì)免疫印跡法檢測(cè)隱丹參酮誘導(dǎo)細(xì)胞凋亡過(guò)程中對(duì)活性氧水平的影響;利用異種移植瘤裸鼠模型檢測(cè)腫瘤生長(zhǎng)情況及藥物毒性作用;利用免疫組織化學(xué)染色法檢測(cè)移植瘤裸鼠的腫瘤組織中MAPK和STAT3信號(hào)通路相關(guān)蛋白的表達(dá)情況。結(jié)果:體外實(shí)驗(yàn)結(jié)果顯示:隱丹參酮對(duì)12種胃癌細(xì)胞均具有良好的殺傷作用;隱丹參酮能夠通過(guò)抑制Bcl-2和pro-caspase-3蛋白的表達(dá);促進(jìn)Bad和cleaved-caspase-3蛋白的表達(dá),誘導(dǎo)胃癌AGS細(xì)胞發(fā)生凋亡;隱丹參酮通過(guò)抑制cyclin B1和CDK 1/2蛋白的表達(dá),誘導(dǎo)胃癌MKN-28細(xì)胞G2/M期周期阻滯;隱丹參酮能夠促進(jìn)p-JNK和p-p38蛋白的表達(dá),抑制p-ERK、p-AKT及p-STAT3的表達(dá);隱丹參酮能夠加劇細(xì)胞內(nèi)活性氧的累積進(jìn)而誘導(dǎo)胃癌細(xì)胞的凋亡。體內(nèi)實(shí)驗(yàn)結(jié)果顯示:隱丹參酮能夠抑制移植瘤裸鼠皮下腫瘤的生長(zhǎng),同時(shí)移植瘤裸鼠體重?zé)o變化,對(duì)血常規(guī)指標(biāo)無(wú)影響,對(duì)主要臟器無(wú)毒副作用;隱丹參酮能夠促進(jìn)移植瘤裸鼠腫瘤組織中p-JNK、p-p38及cleaved-caspase-3蛋白的表達(dá),抑制p-ERK蛋白和p-STAT3蛋白的表達(dá)。結(jié)論:隱丹參酮通過(guò)細(xì)胞內(nèi)活性氧介導(dǎo)的MAPK、AKT及STAT3信號(hào)途徑,誘導(dǎo)胃癌細(xì)胞發(fā)生凋亡及周期阻滯,同時(shí)抑制體內(nèi)腫瘤的生長(zhǎng)。
[Abstract]:Objective: gastric cancer is one of the most common malignant tumors of digestive system. In China, the number of deaths due to gastric cancer is much higher than the world average, which seriously threatens people's health and life. Therefore, it is imperative to find an effective, safe and inexpensive anticancer drug. Cryptotanshinone is a compound monomer extracted from dried root and rhizome of Salvia miltiorrhiza, which has many pharmacological effects, such as antibacterial, anti-inflammatory and anti-cancer, but its specific molecular pharmacological mechanism is not clear. Cryptotanshinone has anti-tumor activity and has been confirmed in lung cancer and prostate cancer cells. In this study, we used xenotransplantation tumor nude mice and gastric cancer cell lines to elucidate the killing effect of cryptotanshinone on gastric cancer cells, blocking cell cycle, inducing apoptosis and related signal transduction pathways at the animal, cellular and molecular levels. To provide a certain theoretical basis for the clinical treatment of gastric cancer. Methods: cell viability was detected by thiazolyl blue colorimetry, apoptosis was detected by Annexin V/PI double staining, flow cytometry and Western blotting. The cell cycle arrest was detected by flow cytometry and Western blotting, and the expression of MAPK K T and STAT3 signal pathway related proteins were detected by Western blotting. Flow cytometry and Western blotting were used to detect the effect of cryptotanshinone on the level of reactive oxygen species (Ros) in the process of apoptosis induced by Cryptotanshinone, and the tumor growth and drug toxicity were detected by xenotransplantation tumor model in nude mice. Immunohistochemical staining was used to detect the expression of MAPK and STAT3 signal pathway related proteins in nude mice. Results: Cryptotanshinone had a good killing effect on 12 kinds of gastric cancer cells in vitro, cryptotanshinone could inhibit the expression of Bcl-2 and pro-caspase-3 protein, promote the expression of Bad and cleaved-caspase-3 protein, induce the apoptosis of gastric cancer AGS cells. Cryptotanshinone induced G _ 2 / M phase arrest in gastric cancer MKN-28 cells by inhibiting the expression of cyclin B1 and CDK 1 / 2 protein, cryptotanshinone promoted the expression of p-JNK and p-p38 protein, and inhibited the expression of p-ERK _ (1) -AKT and p-STAT3. Cryptotanshinone can increase the accumulation of reactive oxygen species and induce apoptosis of gastric cancer cells. The results in vivo showed that Cryptotanshinone could inhibit the growth of subcutaneous tumor in nude mice, while the weight of xenografted nude mice had no change, had no effect on blood routine indexes, and had no toxic and side effects on the main organs. Cryptotanshinone could promote the expression of p-JNK-p38 and cleaved-caspase-3 protein and inhibit the expression of p-ERK protein and p-STAT3 protein in nude mice. Conclusion: Cryptotanshinone induces apoptosis and cell cycle arrest in gastric cancer cells through intracellular reactive oxygen species mediated MAPK- AKT and STAT3 signaling pathway, while inhibiting tumor growth in vivo.
【學(xué)位授予單位】：黑龍江八一農(nóng)墾大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.2

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本文編號(hào)：1814332