Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway  

作　　者：Han-lin Wang Jia-nan Li Wei-juan Kan Gao-ya Xu Guang-hao Luo Ning Song Wen-biao Wu Bo Feng Jing-feng Fu Yu-tong Tu Min-min Liu Ran Xu Yu-bo Zhou Gang Wei Jia Li 

机构地区：[1]School of Pharmacy,Fudan University,Shanghai,210023,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [3]University of Chinese Academy of Sciences,Beijing,100049,China [4]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210023,China [5]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,310000,China [6]School of Life Science and Biopharmaceutics,Shenyang Pharmaceutical University,Shenyang,110016,China [7]School of Pharmaceutical Science,Jiangnan University,Wuxi,214122,China [8]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,528400,China

出　　处：《Acta Pharmacologica Sinica》2023年第11期2296-2306,共11页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China(81821005);Guangdong High-level New R&D Institute(2019B090904008);Guangdong High-level Innovative Research Institute(2021B0909050003);Science and Technology Commission of Shanghai Municipality(18431907100 and 19430750100).

摘　　要：Current therapy for acute myeloid leukemia (AML) is largely hindered by the development of drug resistance of commonly used chemotherapy drugs, including cytarabine, daunorubicin, and idarubicin. In this study, we investigated the molecular mechanisms underlying the chemotherapy drug resistance and potential strategy to improve the efficacy of these drugs against AML. By analyzing data from ex vivo drug-response and multi-omics profiling public data for AML, we identified autophagy activation as a potential target in chemotherapy-resistant patients. In THP-1 and MV-4-11 cell lines, knockdown of autophagy-regulated genes ATG5 or MAP1LC3B significantly enhanced AML cell sensitivity to the chemotherapy drugs cytarabine, daunorubicin, and idarubicin. In silico screening, we found that chloroquine phosphate mimicked autophagy inactivation. We showed that chloroquine phosphate dose-dependently down-regulated the autophagy pathway in MV-4-11 cells. Furthermore, chloroquine phosphate exerted a synergistic antitumor effect with the chemotherapy drugs in vitro and in vivo. These results highlight autophagy activation as a drug resistance mechanism and the combination therapy of chloroquine phosphate and chemotherapy drugs can enhance anti-AML efficacy.

关 键 词：acute myeloid leukemia CYTARABINE DAUNORUBICIN IDARUBICIN drug resistant multi-omics AUTOPHAGY chloroquine phosphate 

分 类 号：R363[医药卫生—病理学]