Artesunate reverses cytarabine resistance in acute myeloid leukemia by blocking the JAK/STAT3 signaling

Although cytarabine (AraC) has greatly contributed to improving the prognosis of patients with acute myeloid leukemia (AML), many patients developed drug resistance and eventually succumbed to AML. Thus, resistance to AraC is a major obstacle to improve the efficacy of chemotherapy in AML. Hence, this study aimed to demonstrate that artesunate (ART) can reliably induce cell death in vitro and block AraC resistance. AML cell lines resistant to AraC were first constructed by repeated dosing for 5 months. Further, we analyzed whether ART intervention affected the sensitivity of AraC-resistant cells to AraC by cell function experiments, mainly including CCK-8 to assess cell viability, flow cytometry to examine apoptosis, and Western blotting to measure the Janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) pathway protein expression. Furthermore, whether JAK/STAT3 pathway knockdown has a blocking effect on the efficacy of ART was also assessed. Co-treatment of ART and AraC increased the sensitivity of AML cells to AraC. Also, it effectively reversed the resistance of AML cells to AraC that is shown by the significantly reduced proliferation and increased apoptosis rates. ART intervention suppressed the activation of the JAK/STAT3 signaling pathway in AraC-resistant AML cells, suggesting that the function of ART in reversing AraC resistance is indeed dependent on the JAK/STAT3 signaling pathway. In summary, ART enhanced the sensitivity of AML/AraC-resistant cells to AraC by modulating the JAK/STAT3 pathway.

尽管阿糖胞苷（cytarabine, AraC）对改善急性髓系白血病（acute myeloid leukemia, AML）患者的预后具有重要价值，但多数患者仍会产生耐药性，最终死于AML。因此，AraC耐药是提升AML化疗疗效的核心障碍。本研究旨在证实青蒿琥酯（artesunate, ART）可在体外稳定诱导细胞死亡，并逆转AraC耐药性。研究团队首先通过连续5个月反复给药的方式，构建了耐AraC的AML细胞系。随后，借助多项细胞功能实验分析ART干预能否增强耐AraC细胞对AraC的敏感性，实验主要包括：采用CCK-8试剂盒评估细胞活力、流式细胞术检测细胞凋亡、蛋白质免疫印迹（Western blotting）检测贾纳斯激酶（Janus kinase, JAK）/信号转导与转录激活因子3（signal transducers and activators of transcription 3, STAT3）通路的蛋白表达水平。此外，本研究还评估了敲低JAK/STAT3通路是否会对ART的药效产生阻断作用。ART与AraC联合给药可提升AML细胞对AraC的敏感性，且能有效逆转AML细胞对AraC的耐药性，具体表现为细胞增殖显著受抑、凋亡率明显升高。ART干预可抑制耐AraC的AML细胞中JAK/STAT3信号通路的激活，这表明ART逆转AraC耐药性的功能确实依赖于JAK/STAT3信号通路。综上，ART可通过调控JAK/STAT3通路，增强耐AraC的AML细胞对AraC的敏感性。