三羟基咔咯及其镓配合物(-Ga)在新型抗肿瘤药物研发中的应用及对人肺癌细胞(A549)增殖的影响  

Application of trihydroxycarbole and its gallium complex(-Ga)in development of new anti-tumor drugs and its effect on the proliferation of human lung cancer cells(A549)

作　　者：张静 赵天 丁亚楠 赵晓飞 ZHANG Jing;ZHAO Tian;DING Yanan;ZHAO Xiaofei(Department of Pharmacy,Xingtai Third Hospital,Xingtai Hebei 054000,China;Department of Clinical Pharmacy,the Second Affiliated Hospital of Xingtai Medical College,Xingtai Hebei 054000,China)

机构地区：[1]邢台市第三医院药剂科,河北邢台054000 [2]邢台医学高等专科学校第二附属医院临床药学科,河北邢台054000

出　　处：《新疆医科大学学报》2021年第3期315-320,共6页Journal of Xinjiang Medical University

基　　金：2020年河北省医学科学研究课题项目(20201593)。

摘　　要：目的探讨三羟基咔咯(咔咯1)及其镓配合物(1-Ga)在新型抗肿瘤药物研发中的应用及对人肺癌细胞(A549)增殖的影响。方法培养人肺癌(A549)细胞,分成对照组、咔咯1组及1-Ga组,采用噻唑蓝比色法(methyl thiazolyl tetrazolium,MTT)测定黑暗和光照条件下3组对A549细胞的毒性作用,并计算和比较咔咯1组及1-Ga组半数最大抑制浓度值(half maximal inhibitory concentration,IC50)值;采用流式细胞术检测咔咯1及1-Ga作用下的A549细胞生长和凋亡情况;于荧光显微镜下对比观察咔咯1及1-Ga对A549细胞形态和线粒体膜电势的影响;另构建异种移植斑马鱼模型,并观察咔咯1、1-Ga对A549细胞生长和转移影响。结果相较于对照组,咔咯1和1-Ga均对A549、MCF-7、HepG23种肿瘤细胞存在光毒性,光照条件下1-Ga对MCF-7、A549肿瘤细胞的IC50小于咔咯1(P<0.05)。光照条件下咔咯1和1-Ga均能抑制A549细胞增殖,A549细胞的外观形态发生明显变化,且1-Ga组细胞形态学变化更显著。光照条件下使用咔咯1和1-Ga处理后的A549肿瘤细胞线粒体膜电势下降,诱导细胞发生凋亡且呈现绿色荧光;且1-Ga组的异种移植斑马鱼模型中A549细胞转移程度相比咔咯1组更低。对照组中99%以上A549细胞存活,咔咯1组、1-Ga组处理过后的A549细胞存活比例均下降,且1-Ga组细胞凋亡比例显著高于咔咯1组(P<0.05)。结论咔咯1及其1-Ga均具有强烈光核酸酶活性,均可通过阻滞细胞周期抑制A549增殖、转移过程,同时可诱导肿瘤细胞发生凋亡,且1-Ga的光核酸酶活性和细胞毒性更强,有望成为一种新型抗肿瘤药物应用于恶性肿瘤的治疗。Objective To explore the application of trihydroxycarbole(carbole 1)and its gallium complex(1-Ga)in the development of new antitumor drugs and the effects on the proliferation of human lung cancer cells(A549).Methods Human lung cancer(A549)cells were cultured.The thiazole blue colorimetric method(MTT)was used to determine the toxic effects of carbole 1 and 1-Ga on A549 cells under dark and light conditions,and the half-maximum inhibitory concentration(IC50)values were calculated and compared.Flow cytometry was used to detect the growth and apoptosis of A549 cells under the effects of carbole 1 and 1-Ga;Under fluorescent microscope,the effect of carbole 1 and1-Ga on A549 cell morphology and mitochondrial membrane potential were observed;In addition,a xenograft zebrafish model was constructed,and the effects of carbole 1,1-Ga on the growth and metastasis of A549 cells were observed.Results The results of in vitro cytotoxicity analysis showed that carbole 1 and 1-Ga were phototoxic on A549,MCF-7,HepG2 tumor cells.Under light conditions,IC50 of 1-Ga to MCF-7 and A549 tumor cells was less than carbole 1(P<0.05).Under light conditions,both carbole 1 and 1-Ga can inhibit the proliferation of A549 cells.The appearance and morphology of A549 cells changed significantly,and the morphological changes of 1-Ga group were more significant.The mitochondrial membrane potential test results showed that the mitochondrial membrane potential of A549 tumor cells after treatment with carbole 1 and 1-Ga under light conditions decreased,inducing cell apoptosis and showing green fluorescence;moreover,the degree of A549 cell migration in the xenograft zebrafish model of the 1-Ga group was lower than that of the carbole 1 group.Flow cytometry results showed that more than 99%of the A549 cells in the control group survived.The survival rate of A549 cells after treatment with carbole 1 and 1-Ga decreased,and the percentage of apoptosis in 1-Ga group was significantly higher than that with carbole 1 group(P<0.05).Conclusion carbole1 and its 1

关 键 词：咔咯 镓 抗肿瘤药物 人肺癌细胞 增殖 抑制 蛋白激酶B 

分 类 号：R963[医药卫生—微生物与生化药学]