Chenwei Yang, Yixin Hu, Li Gao, Zhiheng Li, Yongping Zhang, Ran Zhuo, Yayun Du, Hu Liu, Qi Ji, Minyuan Liu, Jian Pan, Jun Lu, Peifang Xiao, Yuanyuan Tian, Sudan He, Jing Ling, Shaoyan Hu
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引用次数: 0
摘要
急性髓性白血病(AML)是一种需要新型治疗策略的侵袭性造血恶性肿瘤。在这项研究中,我们发现磷酸二酯酶3 A(PDE3A)是治疗急性髓性白血病药物重新定位的潜在新靶点。与正常细胞相比,PDE3A在急性髓细胞白血病细胞中优先过表达,PDE3A的高表达与新发急性髓细胞白血病患者较低的无事件生存期(EFS)相关。PDE3A抑制剂阿那格雷(ANA)能有效抑制PDE3A高表达的AML细胞的增殖,而对PDE3A低表达的细胞影响甚微。此外,在高 PDE3A 表达的 AML 细胞中,还观察到 ANA 与其他化疗药物的协同作用。在所有常用于 AML 细胞系模型的 ANA 化疗药物中,ANA 与idarubicin(IDA)的组合显示出最显著的协同效应。从机理上讲,ANA 和 IDA 的协同作用通过热蛋白沉积抑制了 PDE3A 高的 AML 细胞株的存活。这一机制是由 Caspase-3 激活引发的 GSDME 裂解启动的。与单药和药物对照治疗相比,对高 PDE3A 表达的白血病动物进行体内联合治疗可显著减少白血病负荷并延长存活时间。我们的研究结果表明,对于PDE3A高表达的急性髓细胞白血病患者来说,ANA和IDA联合治疗是一种创新且前景广阔的治疗策略。
Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia
Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy requiring novel treatment strategies. In this study, we identified phosphodiesterase 3 A (PDE3A) as a potential new target for drug repositioning in AML. PDE3A was preferentially overexpressed in AML cells than in normal cells, and high expression of PDE3A was correlated with lower event-free survival (EFS) in de novo AML patients. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells while exhibiting minimal impact on those with low PDE3A expression. Moreover, synergistic effect of ANA with other chemotherapeutic drugs in high PDE3A expression AML cells was observed. The ANA-idarubicin (IDA) combination showed the most remarkable synergistic effect among all ANA-chemotherapeutic drugs commonly used in AML cell line models. Mechanistically, the synergy between ANA and IDA inhibited the survival of PDE3Ahigh AML cell lines through pyroptosis. This mechanism was initiated by GSDME cleavage triggered by caspase-3 activation. In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues