红霉素对钾离子通道HERG高表达癌细胞的增殖抑制及其与化疗药物的协同作用  

Erythromycin inhibits the proliferation of HERG K^+ channel highly expressing cancer cells and shows synergy with anticancer drugs

作　　者：陈淑珍[1] 张胜华[1] 弓建华[1] 甄永苏[1] 

机构地区：[1]中国医学科学院医药生物技术研究所,北京100050

出　　处：《中华医学杂志》2006年第47期3353-3357,共5页National Medical Journal of China

基　　金：国家基础研究"973"项目基金资助项目(2002CB513108);美国癌症研究基金会(NFCR)基金资助项目

摘　　要：目的研究红霉素对钾离子通道HERG高表达癌细胞的增殖抑制及其与化疗药物的协同作用。方法采用Western印迹、四甲基偶氮唑蓝(MTT)法、流式细胞术、细胞黏附实验以及明胶酶谱法观察红霉素对肿瘤细胞的作用。结果HERG钾通道在人结肠癌HT-29细胞和小鼠结肠癌C26细胞中均有表达,和HERG钾通道高表达对照神经母细胞瘤SH-SY5Y相比,在HT-29细胞中表达量较高。红霉素对HT-29细胞和C26细胞的增殖具有不同程度的抑制作用,呈浓度依赖性。红霉素能将HT-29细胞阻滞于G2/M期,并引起明显的SubG1峰。红霉素对HT-29细胞黏附于Ⅰ型胶原具有明显的抑制作用,存在明显的剂量-效应关系。红霉素能抑制肿瘤细胞释放明胶酶MMP-2。红霉素与长春新碱协同抑制小鼠C26细胞的增殖。长春新碱单用以及长春新碱与红霉素(50μmol/L)联用的IC50分别为62.65nmol/L和4.68nmol/L。红霉素与紫杉醇、羟基喜树碱联用亦显示协同作用。结论红霉素在能抑制钾离子通道HERG高表达癌细胞HT-29的增殖,并能诱导肿瘤细胞凋亡。红霉素与长春新碱等化疗药物显示协同作用。Objective To investigate the effects of erythromycin on the proliferation of the human ether-a-go-go related gene （HERG） K^＋ channel highly expressing cancer cells and its synergy with antitumor chemotherapeutic agents. Methods Human fibrosarcoma cell of the line HT-1080, murine colon carcinoma cells of the line C26, human colon carcinoma cells of the line HT-29, human pulmonary epithelial cells of the line A549, and human neuroblastoma cells of the line SH-SY5Y were cultured. Western blotting was used to detect the protein expression of the HERG K^＋ channel protein. Erythromyein, taxol, and vineristine were added into the culture fluid, to observe the proliferation of the cancer cells. Collagen Ⅰ was used to coat 96-well plate, HT-29 cells were put into, and Erythromyein, taxol, and vineristine were added, MTT method was used to examine the cell adhesion. SDS-PAGE was used to detect the secretion of gelatinase. Flow eytometry was used to detect the cell cycle and apeptosis. The coefficient of drug interaction （CDI） was calculated. Results HERG K^＋ channel expression was found in both HT-29 human colon carcinoma cells and C26 murine colon carcinoma cells. The expression level in HT-29 cells was higher than that in the positive control SHSY5Y neuroblastoma cells. Erythromyein suppressed the proliferation of HT-29 and C26 cells in a dose-dependent manner. There existed a remarkable G2/M arrest after the cells were exposed to erythromyein. Induction of apeptosis in HT-29 cells and inhibition of cell adhesion to collagen Ⅰ were found. Erythromyein inhibited the secretion of MMP-2 from HT-29 cells in a dose-dependent manner. At sub-eytotoxie concentration, erythromyein potentiated the eytotoxieity of vineristine, taxol, and hydroxyl-camptothecin to C26 cells. The IC50 values for vineristine and vineristine plus erythromyein （50 μmol/L） were 62. 65 nmoL/L and and 4. 68 nmoL/L respectively. Conclusion Erythromyein inhibits the proliferation and induces the lapeptosis of cancer cells with high HERG

关 键 词：红霉素 肿瘤浸润 凋亡 钾离子通道 

分 类 号：R730.2[医药卫生—肿瘤]