紫杉醇衍生物TM-2体外抑制肿瘤增殖作用及机制研究
发布时间：2018-11-01 13:53
【摘要】：紫杉醇是广谱抗肿瘤药物,其独特的抗癌机理,在临床上相继被证明对卵巢癌、子宫癌、乳腺癌等多种癌症具有较明显的治疗成果,它主要作用于微管蛋白,可以加强微管蛋白聚合,并且阻止其解聚,使细胞的有丝分裂过程受阻,进而导致细胞凋亡,目前在临床上已作为一线用药治疗乳腺癌、卵巢癌和非小细胞肺癌。然而,紫杉醇存在着一定的缺陷,如溶解度和选择性较差,毒副作用较大,使用不方便,易产生耐药性及无法透过血脑屏障等。针对这些问题,研究者从紫杉醇的化学结构、构效关系以及制剂等角度着手研究,研制了一些疗效显著的紫杉醇类似物的新结构及新剂型。本实验是探究不同浓度下的紫杉醇的衍生物(TM-2)对多种肿瘤细胞的抑制作用,及可能作用机制。通过体外细胞培养,应用MTT、CCK-8法检测对观察TM-2对人源性肿瘤细胞人前列腺癌(PC-3)细胞、人卵巢癌(SK-OV-3,A2780)细胞、人宫颈癌(He La)细胞、人乳腺癌(MCF-7)细胞、人结直肠癌(HCT-116)细胞、人肝癌(Hep G2)细胞、人胰腺癌(Bx PC-3)细胞、人肺腺癌(A549)细胞的增殖抑制作用,应用Annexin V-FITC/PI双染、流式细胞术、Western Blot检测TM-2诱导肿瘤细胞凋亡的作用及机制。结果表明TM-2在体外可以明显抑制多种人源性肿瘤细胞的增殖,其作用可能与其激活线粒体和死亡受体途径,上调Bax蛋白表达,下调Bcl-2蛋白表达,降低线粒体膜电位,促进caspase-3的剪切活化诱导细胞凋亡有关。
[Abstract]:Paclitaxel is a broad-spectrum antineoplastic drug with its unique anticancer mechanism, which has been proved to be effective in the treatment of ovarian cancer, uterine cancer, breast cancer and many other cancers. It mainly acts on tubulin. It can enhance tubulin polymerization and prevent it from deaggregating, thus blocking the mitotic process of cells and leading to apoptosis. It has been used as a first-line drug in the treatment of breast cancer, ovarian cancer and non-small cell lung cancer. However, paclitaxel has some defects, such as poor solubility and selectivity, large toxic side effects, inconvenient use, resistance to drug resistance and inability to penetrate the blood-brain barrier. In order to solve these problems, the researchers studied the chemical structure, structure-activity relationship and preparation of paclitaxel, and developed some new structures and formulations of taxol analogues. The aim of this study was to investigate the inhibitory effect of taxol derivatives (TM-2) on various tumor cells and its possible mechanism. Human prostate cancer (PC-3) cells, human ovarian cancer (SK-OV-3,A2780) cells and human cervical cancer (He La) cells were detected by MTT,CCK-8 assay in vitro. The proliferation inhibition of human breast cancer (MCF-7) cells, human colorectal cancer (HCT-116) cells, human hepatocellular carcinoma (Hep G2) cells, human pancreatic cancer (Bx PC-3) cells and human lung adenocarcinoma (A549) cells were detected by Annexin V-FITC/PI double staining. Flow cytometry (FCM), Western Blot was used to detect the apoptosis of tumor cells induced by TM-2. The results showed that TM-2 could significantly inhibit the proliferation of human tumor cells in vitro, which might be related to its activation of mitochondria and death receptor pathway, up-regulation of Bax protein expression, down-regulation of Bcl-2 protein expression, and reduction of mitochondrial membrane potential. Promoting shear activation of caspase-3 induces apoptosis.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R96
本文编号：2304112
[Abstract]:Paclitaxel is a broad-spectrum antineoplastic drug with its unique anticancer mechanism, which has been proved to be effective in the treatment of ovarian cancer, uterine cancer, breast cancer and many other cancers. It mainly acts on tubulin. It can enhance tubulin polymerization and prevent it from deaggregating, thus blocking the mitotic process of cells and leading to apoptosis. It has been used as a first-line drug in the treatment of breast cancer, ovarian cancer and non-small cell lung cancer. However, paclitaxel has some defects, such as poor solubility and selectivity, large toxic side effects, inconvenient use, resistance to drug resistance and inability to penetrate the blood-brain barrier. In order to solve these problems, the researchers studied the chemical structure, structure-activity relationship and preparation of paclitaxel, and developed some new structures and formulations of taxol analogues. The aim of this study was to investigate the inhibitory effect of taxol derivatives (TM-2) on various tumor cells and its possible mechanism. Human prostate cancer (PC-3) cells, human ovarian cancer (SK-OV-3,A2780) cells and human cervical cancer (He La) cells were detected by MTT,CCK-8 assay in vitro. The proliferation inhibition of human breast cancer (MCF-7) cells, human colorectal cancer (HCT-116) cells, human hepatocellular carcinoma (Hep G2) cells, human pancreatic cancer (Bx PC-3) cells and human lung adenocarcinoma (A549) cells were detected by Annexin V-FITC/PI double staining. Flow cytometry (FCM), Western Blot was used to detect the apoptosis of tumor cells induced by TM-2. The results showed that TM-2 could significantly inhibit the proliferation of human tumor cells in vitro, which might be related to its activation of mitochondria and death receptor pathway, up-regulation of Bax protein expression, down-regulation of Bcl-2 protein expression, and reduction of mitochondrial membrane potential. Promoting shear activation of caspase-3 induces apoptosis.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R96
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