小分子化合物LG308抑制前列腺癌生长和转移的研究

发布时间：2018-06-22 02:10

本文选题：前列腺癌 + 微管　；参考：《华东师范大学》2014年硕士论文

【摘要】：对于男性而言,在泌尿生殖系统疾病中,前列腺癌(PCa)是一种对男性健康造成极大威胁的恶性肿瘤。在美国,男性的前列腺癌新发病率占男性所有所患癌症的第一位、其致死率则位居第二位；在中国,近些年来,随着社会的发展,人们生活标准不断提高、饮食方面较以往发生了很大的改变,再加上人口老龄化以及荷尔蒙不当使用等原因,中国男性的前列腺癌发病率显著上升,前景不容乐观,越来越引起人们的重视。目前,临床实践中前列腺癌的治疗方法主要有：手术疗法、放射疗法、激素疗法以及化学药物疗法。手术治疗、放疗和激素治疗能起到一定效果,然而一般情况下,尽管采取了以上措施进行了积极治疗,前列腺癌还是会继续发展、恶化,最终发展成为雄激素非依赖性的前列腺癌(AIPC)。也就是说会导致上述包括激素治疗在内的治疗手段的效果不理想,这时,必须采用化学药物治疗(即化疗)。值得注意的是,在化疗药物中,针对微管发挥作用的抗肿瘤药物(如多西紫杉醇、卡巴他赛)在前列腺癌治疗中发挥了重要作用。其中多西紫杉醇是目前治疗前列腺癌标准的一线化疗药物。我们利用本实验室已有的合成小分子化合物库进行筛选,从中筛选到一个名为LG308的小分子化合物。在体外细胞实验中,该化合物能明显地抑制雄激素依赖性和非依赖性的前列腺癌细胞的增殖和转移并能明显的将癌细胞的细胞周期进程阻滞于G2/M期,进而引起细胞的凋亡、死亡。进一步研究发现LG308对前列腺癌细胞微管的聚合有抑制作用。为了进一步证明LG308对于前列腺癌的抑制效果,我们接下来在动物水平上,通过小鼠皮下荷瘤实验和前列腺癌原位生长、转移实验进一步检测了小分子化合物LG308抑制雄激素非依赖性的前列腺癌(AIPC)的作用效果。结果表明,LG308在动物体内水平同样能发挥抑制前列腺癌生长、转移的作用。综上所述,小分子化合物LG308通过抑制前列腺癌细胞的微管聚合作用达到在体内和体外水平抑制前列腺癌生长转移的效果。本研究发现了一种新的抗前列腺癌的潜在药物,并为靶向微管治疗前列腺癌的药物开发提供了参考。
[Abstract]:Prostate cancer (PCA) is a malignant tumor that poses a great threat to men's health in genitourinary diseases. In the United States, men have the first new incidence of prostate cancer and the second leading cause of death in men. In China, living standards have been rising in recent years as society has developed. The changes in diet and the aging of the population and inappropriate use of hormones, the incidence of prostate cancer in China has increased significantly, the prospects are not optimistic, more and more attention. At present, the treatment of prostate cancer in clinical practice mainly includes surgical therapy, radiotherapy, hormone therapy and chemotherapeutic therapy. Surgery, radiotherapy and hormone therapy can have some effect, but in general, despite the above measures, prostate cancer will continue to develop and worsen. It eventually developed into androgen-independent prostate cancer (AIPC). In other words, these treatments, including hormone therapy, do not work well, and chemotherapeutic therapy (chemotherapy) must be used. Notably, microtubule-specific antitumor drugs (such as docetaxel, carbatin) play an important role in the treatment of prostate cancer in chemotherapeutic drugs. Among them, docetaxel is the standard first-line chemotherapeutic drug for prostate cancer. We selected a small molecular compound named LG308 from the synthetic small molecular compound library. In vitro, the compound can inhibit the proliferation and metastasis of androgen-dependent and non-dependent prostate cancer cells and block the cell cycle progression of cancer cells to G _ 2 / M phase, which leads to apoptosis. Pass away. Further studies have shown that LG308 inhibits the microtubule polymerization of prostate cancer cells. To further demonstrate the inhibitory effect of LG308 on prostate cancer, we then tested subcutaneous tumor implantation in mice and in situ growth of prostate cancer at the animal level. The effect of small molecular compound LG308 on androgen-independent prostate cancer (AIPC) was further examined by metastasis assay. The results showed that LG308 could also inhibit the growth and metastasis of prostate cancer. In conclusion, small molecular compound LG308 inhibits prostate cancer growth and metastasis in vivo and in vitro by inhibiting the microtubule polymerization of prostate cancer cells. In this study, a new potential drug against prostate cancer has been found, which provides a reference for the development of microtubule targeted drug for prostate cancer.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.25

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