School of Pharmacy, Fudan University, Shanghai, 210023, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Acta Pharmacol Sin. 2023 Nov;44(11):2296-2306. doi: 10.1038/s41401-023-01112-8. Epub 2023 Jun 14.
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.
目前，急性髓细胞白血病（AML）的治疗在很大程度上受到常用化疗药物（包括阿糖胞苷、柔红霉素和伊达比星）耐药性发展的阻碍。在这项研究中，我们研究了化疗药物耐药性的分子机制以及提高这些药物治疗 AML 疗效的潜在策略。通过分析 AML 体外药物反应和多组学分析公共数据，我们确定自噬激活是化疗耐药患者的一个潜在靶点。在 THP-1 和 MV-4-11 细胞系中，自噬调控基因 ATG5 或 MAP1LC3B 的敲低显著增强了 AML 细胞对化疗药物阿糖胞苷、柔红霉素和伊达比星的敏感性。在计算机筛选中，我们发现磷酸氯喹模拟了自噬失活。我们表明，磷酸氯喹以剂量依赖的方式下调 MV-4-11 细胞中的自噬途径。此外，磷酸氯喹在体外和体内与化疗药物表现出协同抗肿瘤作用。这些结果强调了自噬激活是一种耐药机制，并且磷酸氯喹与化疗药物的联合治疗可以增强抗 AML 疗效。
