紫草素衍生物SYUNZ-7的抗肿瘤作用及其机制的初步研究  

Antitumor Effect and Mechanism of Shikonin Derivative SYUNZ-7

作　　者：黄河[1,2] 谢冰芬[1,2] 朱孝峰[1,2] 冯公侃[1,2] 周军民[1,2] 王一[1,2] 吴海强[3] 黄志纾[3] 古练权[3] 刘宗潮[1,2] 

机构地区：[1]华南肿瘤学国家重点实验室 [2]中山大学肿瘤防治中心实验研究部,广东广州510060 [3]中山大学化学与化学工程学院

出　　处：《癌症》2005年第12期1453-1458,共6页Chinese Journal of Cancer

基　　金：国家自然科学基金项目(No.30271601;No.20272085)~~

摘　　要：背景与目的:实验证明天然紫草素类化合物及其衍生物具有不同程度的细胞毒作用和抗肿瘤作用。本实验研究紫草素萘茜类衍生物[2或3,11-双苯硫基-6-异己萘茜]代号为SYUNZ-7的体内外抗肿瘤作用,并探讨其作用机制。方法:应用MTT法检测SYUNZ-7对多种肿瘤细胞的体外抗增殖作用,并计算IC50值;用小鼠移植肿瘤模型和人鼻咽癌裸鼠移植瘤模型进行SYUNZ-7的体内抗瘤实验;流式细胞术检测细胞凋亡和细胞周期的变化;免疫组化法检测SYUNZ-7对血管生成的影响。结果:SYUNZ-7对人肺癌细胞GLC-82、人鼻咽癌细胞CNE2、人口底癌细胞KB、人胃癌细胞MGC-803和人肝癌细胞HepG2的IC50值分别为(2.18±0.04)μg/ml、(4.17±0.09)μg/ml、(5.41±0.10)μg/ml、(6.41±0.14)μg/ml和(9.99±0.21)μg/ml。SYUNZ-7对GLC-82细胞的体外抗增殖作用最强。小鼠艾氏腹水癌EAC(实体型)抗瘤实验结果显示,在1mg/kg、2mg/kg、4mg/kg和8mg/kg的剂量下SYUNZ-7的抑瘤率分别为(40.5±0.1)%、(50.9±2.3)%、(61.3±1.8)%和(65.6±7.4)%(P<0.01)。1mg/kg、2mg/kg和4mg/kg的SYUNZ-7对CNE2细胞裸小鼠移植瘤的抑瘤率分别为24.7%、38.3%和41.2%(P<0.05)。流式细胞术检测结果显示,SYUNZ-7能浓度依赖性和时间依赖性诱导CNE2细胞的凋亡;随着作用时间的延长或处理浓度的增加,SYUNZ-7可以阻滞CNE2细胞由S期向G2/M期转化。免疫组化结果显示:SYUNZ-7能够呈浓度依赖性抑制CNE2细胞裸小鼠移植瘤的血管生成。结论:紫草素萘茜类衍生物SYUNZ-7具有较强的体内外抗瘤作用,其抗瘤机制与诱导细胞凋亡、阻滞细胞周期和抑制血管生成有关。BACKGROUND ＆ OBJECTIVE： Natural shikonin compounds and their derivatives have cytotoxicity and antitumor effects. This study was to explore in vitro and in vivo antitumor effects of SYUNZ-7 [2 or 3, 11-bis （phenylsulfanyl）-6-isohexenylnaphthazarin] and the mechanisms. METHODS： In vitro antiproliferation effects of SYUNZ-7 on human lung adenocarcinoma cell line GLC-82, human nasopharyngeal cancer cell line CNE2, human oral cavity cancer cell line KB, human gastric cancer cell line MGC-803 and human hepatocellular cancer cell line HepG2 were tested by MTT assay. In vivo antitumor effect of SYUNZ-7 was tested using ascitic cancer EAC xenograft in mice and CNE2 xenograft in nude mice models. Cell apoptosis and cell cycle distribution were assessed by flow cytometry. The in vivo effect of SYUNZ-7 on angiogenesis was detected by immunohistochemistry. RESULTS： The 50% inhibitory concentrations （IC50） of SYUNZ-7 to GLC-82, CNE2, KB, MGC-803, and HepG2 cells were （2.18±0.04） μg/ml, （4.17±0.09） μg/ml, （5.41±0.10） μg/ml, （6.41±0.14） μg/ml, and （9.99±0.21） μg/ml, respectively. Under the treatment of 1, 2, 4, and 8 mg/kg of SYUNZ-7, the inhibitory rates of EAC xenografts in mice were （40.5±0.14）%, （50.9±2.3）%, （61.7±1.8）%, and （65.6±7.4）%, respectively （P〈0.01）. Under the treatment of 1, 2, and 4 mg/kg of SYUNZ-7, the inhibitory rates of CNE2 xenografts in nude mice were 24,7%, 38,3%, and 41,2%, respectively （P〈0.05）. SYUNZ-7 induced apoptosis of CNE2 cells in time- and concentration-dependent manners, and blocked the transition of CNE2 cells from S to G2/M phase. SYUNZ-7 also inhibited the angiogenesis of CNE2 xenografts in nude mice in a concentration-dependent manner. CONCLUSION： SYUNZ-7 has strong in vivo and in vitro antitumor effects which are related to inducing cell apoptosis, blocking cell cycle, and inhibiting angiogenesis of tumor.

关 键 词：SYUNZ-7/药理学 鼻咽肿瘤 移植瘤 细胞凋亡 血管生成 小鼠 

分 类 号：R285[医药卫生—中药学]