新型吲哚酮类衍生物诱导肿瘤细胞凋亡的机制研究

项目名称： 新型吲哚酮类衍生物诱导肿瘤细胞凋亡的机制研究

项目编号： No.31301142

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 滕玉鸥

作者单位： 天津科技大学

项目金额： 25万元

中文摘要： p53基因缺失/变异肿瘤细胞的耐药性机制及其对策是目前肿瘤生物学的研究热点和难点。我们发现新型吲哚酮类衍生物HKL-3e能高效高选择性杀伤p53异常的K562细胞（IC50=4 nM），并诱导该细胞发生Caspase不依赖性凋亡、促进凋亡诱导因子AIF转位。HKL-3e诱导的凋亡不依赖于p53信号通路，也没有Caspase的切割活化，表明其抗肿瘤机制与常规化药不同，很可能与其高效高选择性杀伤p53异常肿瘤细胞的特性有关，尚需深入研究。本项目拟利用HKL-3e选择性杀伤53异常耐药性肿瘤细胞模型，研究以下问题：（1）阐明HKL-3e引发肿瘤细胞凋亡的机理，明确其诱导的凋亡是否是其抗肿瘤的重要机制。（2）探究HKL-3e调控p53下游通路使耐药肿瘤细胞发生凋亡的具体机制。（3）明确HKL-3e是否是通过影响Bcl-2家族或calpains/Cathepsins家族促进AIF转位引发凋亡的。

中文关键词： 吲哚酮；抗肿瘤；作用机制；；

英文摘要： Abnormal of the tumor suppressor p53 is well assosiated with chemotherapy resistance of tumor cells. In our previous works, we designed and synthesized a series of isatin derivatives .The HKL-3e exhibited the highest cytotoxic activityaganist K562 cell lines (IC50=4 nM) . The observed cytotoxic effect in K562 cells was associated with a decrease of cell viability, leading to apoptotic cell death characterized DNA fragmentation. Pretreatment of K562 cells with pan caspase inhibitor, z-VAD did not inhibit HKL-3e induced apoptosis. Furthermore, HKL-3e induced the translocation of apoptosis-inducing factor (AIF) from mitochondria to nucleus, which was indicative of caspase-independent apoptotic cell death. Taken together, Our findings demonstrated that HKL-3e may trigger caspase-independent and AIF-mediated apoptotic cell death in K562 cells. Our study also revealed that human myeloblastic leukemia HL-60 and colon carcinoma HT-29 cells underwent morphological changes characteristic of apoptosis after HKL-3e treatment. These three cell lines lack functional p53, and K562 and HT29 cells are usually resistant to apoptosis. These data suggest that a wider understanding of HKL-3e-induced apoptosis is could theoretically pave the way for the development of new drugs that modulate apoptosis. The aim of this study

英文关键词： isatin；antitumor；mechanism；；