Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways
Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways
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DOI：
10.1038/s41418-019-0465-8
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Fulda, Simone
中科院分区：
文献类型：
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作者：
Dittman, Jessica;Haydn, Tinka;Fulda, Simone
第一代低甲基化药物（HMAs）在老年急性髓细胞白血病（AML）患者中的疗效有限。因此，迫切需要与靶向治疗相结合的策略。在这里，我们发现用SGI-110（guadecitabine）（下一代HMA）引发AML细胞对ASTX 660敏感，ASTX 660是细胞凋亡抑制蛋白1和2（cIAP 1/2）和X连锁IAP（XIAP）的新型拮抗剂。重要的是，SGI-110和ASTX 660协同诱导一组AML细胞系以及原代AML样品中的细胞死亡，同时在很大程度上保留正常的CD 34+人祖细胞，强调了这种组合的翻译相关性。无偏转录组分析显示，SGI-110单独或与ASTX 660组合上调了外源性和内源性凋亡信号通路的关键调节因子的表达，如TNFRSF 10 B（DR 5）、FAS和BAX。死亡受体TNFR 1、DR 5和FAS的单独敲低显著降低了SGI-110/ASTX 660介导的细胞死亡，而肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）或FAS配体（FASLG）的阻断抗体未能提供保护。此外，TNF α阻断抗体Enbrel对SGI-110/ASTX 660诱导的细胞死亡几乎没有保护作用。此外，SGI-110和ASTX 660协同作用以促进胱天蛋白酶-8和BID的切割，从而提供了外在和内在凋亡途径之间的联系。一致地，用SGI-110和ASTX 660顺序处理触发线粒体膜电位（MMP）和BAX活化的损失，这有助于细胞死亡，因为BAX沉默显著保护免于SGI-110/ASTX 660介导的细胞凋亡。总之，这些事件最终导致半胱天冬酶-3/-7活化、核碎裂和细胞死亡。总之，SGI-110和ASTX 660通过参与外在和内在凋亡途径协同诱导AML细胞凋亡，突出了这种组合对AML的治疗潜力。
Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS, and BAX. Individual knockdown of the death receptors TNFR1, DR5, and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASLG) failed to provide protection. Also, TNF alpha-blocking antibody Enbrel had little protective effect on SGI-110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660-triggered loss of mitochondrial membrane potential (MMP) and BAX activation which contributes to cell death, as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in the activation of caspases-3/-7, nuclear fragmentation, and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.