摘要
探讨力达霉素(LDM)对钾离子通道HERG高表达肿瘤细胞的增殖抑制及其与化疗药物的协同作用。用MTT法观察LDM和多种抗癌药的联合应用对人A549和HT-29细胞以及转染HERG钾通道A549细胞的抑制作用;用人结肠癌HT-29裸鼠模型,观察LDM和HCPT联合的抑瘤作用,用药物相互作用指数评价药物联合作用。LDM显著抑制A549细胞和HT-29细胞的增殖,其IC50值分别为2.14和4.64 ng.mL-1,其对HERG钾通道高表达的HT-29细胞的增殖抑制作用弱于对HERG钾通道低表达A549细胞的作用;从IC50值来看,LDM也能抑制HERG钾通道稳定转染的A549细胞的增殖,但这种抑制作用明显弱于稳定转染了空白质粒的A549细胞;LDM分别与氟尿嘧啶(5-FU)、多柔比星(DOX)、羟喜树碱(HCPT)联用,能协同抑制HERG钾通道高表达的HT-29细胞的增殖。LDM与5-FU联用,CDI值均大于0.75;LDM与DOX联用,CDI值均大于0.70;LDM与HCPT联用,CDI值小于0.70;其中,与HCPT联用的协同作用效果最强。5-FU对肿瘤细胞的生长抑制作用不受HERG钾通道的调节,DOX的化疗敏感性与HERG钾通道的表达呈负相关,HERG钾通道的表达正向调节HCPT的化疗敏感性。体内裸鼠实验结果表明,LDM与HCPT对移植于裸鼠的人结肠癌HT-29分别有中度抑制肿瘤生长作用,且两药联合CDI值小于1,存在协同抑瘤作用。HERG钾离子通道的表达水平负向调节肿瘤细胞对LDM的化疗敏感性,与化疗敏感性受到HERG钾离子通道正向调节的HCPT合用时,体外协同作用非常明显;LDM与HCPT联合用药,在体内也显示有协同抗肿瘤作用。HERG钾离子通道可能成为抗肿瘤药物联合作用的选药靶点。
This study is to investigate inhibitory effects of lidamycin（LDM） on the proliferation of HERG K＋ channel highly expressing cancer cells and its synergy with anticancer drugs.MTT assay was used to examine the inhibitory effects of lidamycin combined with various anticancer drugs on the proliferation of human lung cancer A549 cells,human colon cancer HT-29 cells and herg-stably-transfected A549 cells.Using the xenograft model of subcutaneously transplanted HT-29 in nude mice,inhibitory effect was appraised in vivo.The coefficient of drug interaction（CDI） was used to evaluate the synergistic effect of drug combination.LDM significantly inhibited the proliferation of A549 cells and HT-29 cells with IC50 values of 2.14 and 4.64 ng·mL-1,respectively.The efficacy in HT-29 cells with high HERG potassium expression level is less potent than that in A549 cells with low expression level.In terms of IC50 values,LDM suppressed the growth of herg-stably-transfected A549 cells less potently than pCDNA3.1-stably-transfected A549 cells.There existed synergistic effects in the combinations of fluorouracil（5-FU） and LDM,doxorubicin（DOX） and LDM,or hydroxycampto-thecine（HCPT） and LDM.CDI values of the combinations of 5-FU and LDM were more than 0.75.CDI values of LDM and DOX were more than 0.70,but some CDI values of LDM and HCPT were less than 0.70.As for the CDI values,synergistic effects of the combination of LDM and HCPT were the most potent of the three groups.There is no relationship between the inhibitory effect of the growth of cancer cells by 5-FU and HERG potassium expression level.HERG expression level negatively correlated with inhibitory effect on the proliferation of cancer cells by DOX.HERG expression levels and chemosensitivity were positively correlated for HCPT.In the model of subcutaneously xenograft transplanted HT-29 in vivo,LDM and/or HCPT effectively inhibited the growth of HT-29 in nude mice,and the optimum CDI of the combination of LDM and HCPT was less than 1.HERG expression level negatively correlates the chemosensitivity of cancer cells to LDM.There exist synergistic effects in vitro and in vivo in the combination of LDM and HCPT,which inhibitory effects of the proliferation of cancer cells positively modulated by HERG potassium expression level.HERG K＋ channel may become a target of combined therapy for choosing anticancer drugs.
出处
《药学学报》
CAS
CSCD
北大核心
2011年第11期1321-1325,共5页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81072664)
