IAPs小分子抑制剂SM-164增敏骨肉瘤阿霉素治疗与逆转耐药的实验研究

项目名称： IAPs小分子抑制剂SM-164增敏骨肉瘤阿霉素治疗与逆转耐药的实验研究

项目编号： No.81460406

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨东

作者单位： 南昌大学

项目金额： 48万元

中文摘要： 骨肉瘤（OS）是最常见的原发恶性骨肿瘤，凋亡通路异常等原因导致的化疗耐药严重影响OS的治疗效果。阿霉素（ADM）治疗OS也存在同样的问题。OS存在IAPs高表达，SM-164是一种功能强大的Smac模拟物，能解除IAPs对caspase的抑制，促进数种肿瘤细胞凋亡，然而，其在OS的化疗增敏和耐药中的作用仍不明确。本课题组前期实验发现SM-164具有增敏ADM的效应。本项目拟进一步分析关键效应IAPs和主要凋亡通路；建立OS的ADM耐药株，观察SM-164延缓OS耐药产生，逆转耐药株对ADM的抗药性，分析相关作用通路；检测主要IAPs的表达和关键caspase的变化，使用siRNA负向调控、质粒转染正向调控关键通路步骤，阐明重要通路基因蛋白与SM-164效应的因果关系，并通过动物实验验证体内作用效果。项目的成功实施，将阐述SM-164在OS的作用机制，为SM-164的临床使用做出有益的探索。

中文关键词： C18_骨肿瘤；骨肉瘤；阿霉素；Smac模拟物

英文摘要： Osteosarcoma(OS) is the most common primary malignancy of bone. The chemotherapy resistance mainly generated from the abnormal apoptosis pathway has a strong impact on the therapeutic. It is the same circumstance for the Adriamycin（ADM）treatment of OS. There are high expressions of IAPs in OS. SM-164 is a powerful Smac mimetic, it could release the inhibition on caspases by by IAPs, thereby accelerating the apoptosis in tumor cells. However, if the machanism of the ADM sensitivity and resistance effect is still inexplicit. It is found that SM-164 have an effect on increasing ADM sensitivity on curing OS in our preliminary experiments. In this project, we will make further analysis on critical effection and main apoptosis pathway firstly. Secondly, we are going to set up the ADM resistant human OS cell lines, and observe the effects and mechanisms of SM-164 on postponing and reversing the ADM resistance. Thirdly, we plan to analysis relative effect pathway, detect the main IAPs expression and critical Caspase alteration, use negative control by siRNA silencing or overexpression approach by transfected with adenovirus express on vector to determine if its blockage abrogates or promotes SM-164 chemotherapy sensitivity and reversal of ADM resistance, clarify the causality between key genes and SM-164 effect. Lastly and the internal effect will be verified via the experiments on animals. The successful implementation of this project will elaborate the effect mechanism of Smac mimetics used in OS cells, and it will be a beneficial exploration for Smac mimetics acting as a novel drugs for clinic treatment against OS cells.

英文关键词： Bone tumor;Osteosarcoma;Adriamycin;Smac mimetic