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

Acta Pharmacologica Sinica volume 44, pages 2296–2306 (2023)Cite this article

Abstract

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.

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Fig. 1: Identification of targets for chemotherapy resistance in AML primary cells.
Fig. 2: Identification of targets for chemotherapy resistance in AML cell lines.
Fig. 3: The knockdown of autophagy-related genes enhanced chemotherapy drug efficacy.
Fig. 4: Repurposing drugs targeting chemotherapy resistance-associated genes enhances the anti-AML efficacy of chemotherapy drugs in vitro.
Fig. 5: Apoptosis induction by combination of PCQ and chemotherapy drugs and synergistic effect of PCQ and Ara-C in vivo.

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Acknowledgements

This work was 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).

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Authors and Affiliations

  1. School of Pharmacy, Fudan University, Shanghai, 210023, China

    Han-lin Wang, Gang Wei & Jia Li

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Han-lin Wang, Wei-juan Kan, Guang-hao Luo, Ning Song, Wen-biao Wu, Bo Feng, Jing-feng Fu, Yu-tong Tu, Min-min Liu, Ran Xu, Yu-bo Zhou & Jia Li

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Han-lin Wang, Guang-hao Luo, Wen-biao Wu, Jing-feng Fu, Yu-tong Tu, Yu-bo Zhou & Jia Li

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Jia-nan Li, Gao-ya Xu, Ran Xu, Yu-bo Zhou & Jia Li

  5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China

    Guang-hao Luo, Wen-biao Wu & Jia Li

  6. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Bo Feng & Jia Li

  7. School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China

    Min-min Liu

  8. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Yu-bo Zhou & Jia Li

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  1. Han-lin Wang
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Contributions

These authors participated in conception and design: YBZ, JL, HLW. These authors participated in bioinformatics data analysis: HLW, GHL. These authors participated in development of methodology: HLW, WJK, JNL, GYX, NS, GHL, WBW, BF, JFF, YTT, MML, RX. These authors participated in analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): YBZ, JL, HLW, GHL, JNL. These authors participated in writing, review, and/or revision of the manuscript: YBZ, HLW, JL, GW, JNL. These authors participated in study supervision: YBZ, JL, GW.

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Correspondence to Yu-bo Zhou, Gang Wei or Jia Li.

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Wang, Hl., Li, Jn., Kan, Wj. et al. Chloroquine enhances the efficacy of chemotherapy drugs against acute myeloid leukemia by inactivating the autophagy pathway. Acta Pharmacol Sin 44, 2296–2306 (2023). https://doi.org/10.1038/s41401-023-01112-8

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