机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States,[2]The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People’s Hospital, Shenzhen, China,深圳市人民医院深圳医学信息中心[3]Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China,[4]Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China深圳市中医院深圳医学信息中心
M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.
基金：
Science and Technology Science Foundation of Guangzhou [201804010005]; Department of Pharmaceutical Science, St. John's University
第一作者机构：[1]Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, United States,
通讯作者：
推荐引用方式(GB/T 7714)：
Wu Zhuo-Xun,Peng Zheng,Yang Yuqi,et al.M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells[J].FRONTIERS IN ONCOLOGY.2020,10:doi:10.3389/fonc.2020.00674.
APA：
Wu, Zhuo-Xun,Peng, Zheng,Yang, Yuqi,Wang, Jing-Quan,Teng, Qiu-Xu...&Chen, Zhe-Sheng.(2020).M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.FRONTIERS IN ONCOLOGY,10,
MLA：
Wu, Zhuo-Xun,et al."M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells".FRONTIERS IN ONCOLOGY 10.(2020)
