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

Han-lin Wang1,2,3, Jia-nan Li4, Wei-juan Kan2, Gao-ya Xu4, Guang-hao Luo2,3,5, Ning Song2, Wen-biao Wu2,3,5, Bo Feng2,6, Jing-feng Fu2,3, Yu-tong Tu2,3, Min-min Liu2,7, Ran Xu2,4, Yu-bo Zhou2,3,4,8, Gang Wei1, Jia Li1,2,3,4,5,6,8
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
Correspondence to: Yu-bo Zhou:, Gang Wei:, Jia Li:,
DOI: 10.1038/s41401-023-01112-8
Received: 19 January 2023
Accepted: 16 May 2023
Advance online: 14 June 2023


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.
Keywords: acute myeloid leukemia; cytarabine; daunorubicin; idarubicin; drug resistant; multi-omics; autophagy; chloroquine phosphate

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