Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
Mol Pharm. 2012 Jul 2;9(7):1971-82. doi: 10.1021/mp2006714. Epub 2012 Jun 13.
Imidazopyridine CCT129202 is an inhibitor of Aurora kinase activity and displays a 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 ABCB1 overexpressing KBv200 cell xenografts in nude mice and human esophageal cancer tissue overexpressing ABCB1 ex vivo, respectively. Furthermore, the ATPase activity of ABCB1 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.
咪唑并吡啶 CCT129202 是一种 Aurora 激酶活性抑制剂，在临床前研究中显示出良好的抗肿瘤作用。在这里，我们研究了 CCT129202 对多药耐药（MDR）细胞中 ABC 转运体过表达和癌症干细胞样细胞的细胞毒性的增强作用。超过 90%细胞存活浓度的 CCT129202 显著增强了底物药物的细胞毒性，并增加了 ABCB1 和 ABCG2 过表达细胞中多柔比星和罗丹明 123 的细胞内积累，而对亲本敏感细胞没有影响。有趣的是，CCT129202 还增强了癌症干细胞样细胞对多柔比星的敏感性。重要的是，CCT129202 分别增加了 Vincristine 和紫杉醇对裸鼠 ABCB1 过表达 KBv200 细胞异种移植物和体外过表达 ABCB1 的人食管癌细胞的抑制作用。此外，CCT129202 抑制了 ABCB1 的 ATP 酶活性。同源建模预测了 CCT129202 在 ABCB1 大疏水性腔中的结合构象。另一方面，CCT129202 在逆转 MDR 浓度下，既没有明显改变 MDR 细胞中 ABCB1 和 ABCG2 的表达水平，也没有抑制 Aurora 激酶的活性。总之，CCT129202 通过抑制其转运体的功能，显著逆转了 ABCB1 和 ABCG2 介导的体外、体内和体外 MDR，并增强了化疗药物对癌症干细胞样细胞的清除作用。CCT129202 可能是一种有前途的逆转多药耐药的候选药物，用于抗肿瘤联合治疗，值得进一步临床研究。
