Liu Kun, Li Yan-Chi, Chen Yu, Shi Xiao-Bao, Xing Zi-Hao, He Zheng-Jie, Wang Sheng-Te, Liu Wei-Jing, Zhang Peng-Wei, Yu Ze-Zhong, Mo Xue-Mei, Chen Mei-Wan, Chen Zhe-Sheng, Shi Zhi
Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou, China.
Front Oncol. 2021 May 20;11:680663. doi: 10.3389/fonc.2021.680663. eCollection 2021.
Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer.
结直肠癌是一种常见的恶性肿瘤，在全球所有癌症中发病率排名第三，死亡率排名第二。结直肠癌中的化疗耐药是导致高死亡率的一个重要因素。ATP结合盒（ABC）超家族G成员2（ABCG2）通过降低多种化疗药物的细胞内含量赋予多药耐药性（MDR）。开发新型ABCG2抑制剂已成为一种可行的克服耐药性的策略。在本研究中，建立了一种ABCG2基因敲除的结直肠癌细胞系以辅助抑制剂筛选。此外，我们发现共济失调毛细血管扩张症突变（ATM）激酶抑制剂AZ32可通过将米托蒽醌和阿霉素等ABCG2底物化疗药物保留在细胞内，使过表达ABCG2的结直肠癌细胞对这些药物敏感。蛋白质印迹分析表明AZ32不会改变ABCG2的表达。此外，分子对接分析预测AZ32稳定位于ABCG2的跨膜结构域。总之，我们的结果表明AZ32可有效逆转结直肠癌中ABCG2介导的多药耐药。
