Enhancing Chemosensitivity in ABCB1-and ABCG2-Overexpressing Cells and Cancer Stem-Like Cells by An Aurora Kinase Inhibitor CCT129202
Imidazopyridine CCT129202 is an inhibitor of Aurora kinase activity and displays favorable antineoplastic effect in preclinical studies.Here,we investigated the enhanced effect of CCT129202 on the cytotoxicity of chemotherapeutic drugs in multidrug resistant (MDR) cells with overexpression of ATP-binding cassette (ABC) transporters and cancer stem-like cells.CCT129202 of more than 90% cell survival concentration significantly enhanced the cytotoxicity of substrate-drugs and increased the intracellular accumulations of doxorubicin and rhodamine 123 in ABCB1 and ABCG2 overexpressing cells,while no effect was found on parental sensitive cells.Interestingly,CCT129202 also potentiated the sensitivity of cancer stem-like cells to doxorubicin.Importantly,CCT129202 increased the inhibitory effect of vincristine and paclitaxel on ABCBI overexpressing KBv200 cell xenografts in nude mice and human esophageal cancer tissue overexpressing ABCB1 ex-vivo,respectively.Furthermore,the ATPase activity of ABCBI was inhibited by CCT129202.Homology modeling predicted the binding conformation of CCT129202 within the large hydrophobic cavity of ABCB1.On the other hand,CCT129202 neither apparently altered the expression levels of ABCB1 and ABCG2,nor inhibited the activity of Aurora kinases in MDR cells under the concentration of reversal MDR.In conclusion,CCT129202 significantly reversed ABCB1-and ABCG2-mediated MDR in vitro,in vivo and ex-vivo by inhibiting the function of their transporters and enhanced the eradication of cancer stem-like cells by chemotherapeutic agents.CCT129202 may be a candidate as MDR reversal agent for antineoplastic combination therapy and merits further clinical investigation.
CCT129202 Multidrug resistance ATP-binding cassette transporters Aurora kinase inhibitor cancer stem-like cells
Zhen-guo Liu Chao Cheng
Department of Thoracic Surgery,the First Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China
国内会议
2012医学科学前沿暨第二届个体化治疗与抗肿瘤药物研究新趋向研讨会
深圳
英文
273-301
2012-07-13（万方平台首次上网日期，不代表论文的发表时间）