阿那格雷和伊达比星组合可诱导 GSDME 介导的细胞焦亡，作为高 PDE3A 急性髓系白血病的潜在疗法。
Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia.
发表日期：2024 Oct 15
作者：
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
来源：
LEUKEMIA
摘要：
急性髓系白血病（AML）是一种侵袭性造血系统恶性肿瘤，需要新的治疗策略。在这项研究中，我们确定磷酸二酯酶 3 A (PDE3A) 是 AML 药物重新定位的潜在新靶点。与正常细胞相比，PDE3A 在 AML 细胞中优先过表达，并且 PDE3A 的高表达与新发 AML 患者较低的无事件生存期 (EFS) 相关。 PDE3A 抑制剂阿那格雷 (ANA) 可深度抑制高 PDE3A 表达的 AML 细胞的增殖，同时对低 PDE3A 表达的细胞影响极小。此外，在高 PDE3A 表达的 AML 细胞中观察到 ANA 与其他化疗药物的协同作用。在AML细胞系模型中常用的所有ANA化疗药物中，ANA-伊达比星（IDA）组合显示出最显着的协同效应。从机制上讲，ANA 和 IDA 之间的协同作用通过焦亡抑制 PDE3Ahigh AML 细胞系的存活。该机制是由 caspase-3 激活触发的 GSDME 裂解启动的。与单一药物和媒介物对照治疗相比，对高 PDE3A 表达的白血病动物进行体内联合治疗可显着降低白血病负担并延长生存时间。我们的研究结果表明，ANA 和 IDA 联合治疗对于 PDE3A 高表达的 AML 患者来说是一种创新且有前景的治疗策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。
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.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.