【摘 要】
：
目的 探讨蟾毒内酯化合物抗肿瘤作用及其作用机理.方法 ①采用MTT法和肿瘤细胞裸鼠异种移植瘤评价蟾毒内酯类化合物的体外体内抗肿瘤活性.②联合采用鸡胚尿囊膜模型和Transwell小室法评价沙蟾毒精对新生血管和细胞迁移及侵袭的影响.③运用流式细胞术、Annexin V-FITC/PI双染色法和透射电镜检测细胞周期、凋亡和自噬现象.④运用siRNA基因沉默技术、免疫荧光法、Western blot及R
【机 构】
：
暨南大学药学院,广东广州 510632 暨南大学医学院,广东广州 510632
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目的 探讨蟾毒内酯化合物抗肿瘤作用及其作用机理.方法 ①采用MTT法和肿瘤细胞裸鼠异种移植瘤评价蟾毒内酯类化合物的体外体内抗肿瘤活性.②联合采用鸡胚尿囊膜模型和Transwell小室法评价沙蟾毒精对新生血管和细胞迁移及侵袭的影响.③运用流式细胞术、Annexin V-FITC/PI双染色法和透射电镜检测细胞周期、凋亡和自噬现象.④运用siRNA基因沉默技术、免疫荧光法、Western blot及RT-PCR检测相关信号通路蛋白的变化.⑤采用彗星实验、ITC和光谱法研究其对DNA的作用.结果 ①体外活性筛选发现大部分蟾毒内酯化合物均能有效抑制肿瘤细胞增殖,其中沙蟾毒精和蟾毒它灵具有良好的体内抗肿瘤活性[1-7].②沙蟾毒精可抑制肝癌细胞的粘附、运动、迁移和侵袭,也可抑制肿瘤血管新生[10-12].③研究发现该类化合物可阻滞肝癌细胞于G2/M期,诱导肿瘤细胞凋亡和自噬[15,6,11].④作用机制研究发现蟾毒内酯化合物可通过激活ClC-3型氯离子通道,抑制PI3K/Akt/mTOR通路的活化,mTOR可能同时参与沙蟾毒精诱导的凋亡和自噬,且自噬可能拮抗沙蟾毒精诱导的凋亡[12-14].⑤沙蟾毒精和嚏根草素可导致DNA损伤,启动ATM/ATR-Chkl/Chk2-Cdc25C信号通路抑制抑制CDKl-Cyclin B1酶的激活[13]；光谱法研究结果显示沙蟾毒精可以插入DNA链；Molecular modeling模拟了沙蟾毒精的吡喃环部分可以与DNA链中GT碱基对形成氢键.结论 以上研究结果 揭示了蟾毒内酯类化合物抗肿瘤作用的分子机制,为蟾毒内酯类化合物作为抗癌药物的研究开发和临床应用提供理论基础.
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