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

Abstract

Objectives: 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. Methods: 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. Results: 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. Conclusions: In summary, ART enhanced the sensitivity of AML/AraC-resistant cells to AraC by modulating the JAK/STAT3 pathway.