RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis
RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis
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DOI：
10.1038/leu.2011.353
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发表时间：
2012-05-01
期刊：
影响因子：
11.4
通讯作者：
Fulda, S.
中科院分区：
文献类型：
--
作者：
Loeder, S.;Fakler, M.;Fulda, S.
细胞凋亡的逃避可能导致儿童急性淋巴细胞白血病（ALL）的治疗反应差，需要新的治疗策略。在这里，我们报告，细胞凋亡抑制剂（IAP）在亚毒性浓度与各种抗癌药物（即，阿糖胞苷，吉西他滨，环磷酰胺，多柔比星，依托泊苷，阿糖胞苷和紫杉醇）合作，以协同的方式诱导ALL细胞凋亡的组合指数计算，并减少长期的克隆生存。重要的是，我们确定RIP 1作为IAP抑制剂和AraC的这种协同作用的关键调节剂，其通过肿瘤坏死因子-α（TNF α）的自分泌/旁分泌环介导RIP 1/FADD/半胱天冬酶-8复合物的形成。RIP 1的敲除消除了该复合物的形成以及随后的半胱天冬酶-8和-3的活化、线粒体扰动和凋亡。类似地，通过Necrostatin-1抑制RIP 1激酶活性或通过Enbrel阻断TNF α可抑制IAP受体和AraC触发的RIP 1、FADD和caspase-8的相互作用和细胞凋亡。与恶性细胞相反，等摩尔浓度的IAP抑制剂和AraC对正常外周血淋巴细胞或间充质基质细胞无毒。因此，我们的研究结果提供了第一个证据，IAP抑制剂提出了一个有前途的策略，以总理儿童ALL细胞化疗诱导的凋亡，在RIP 1依赖性的方式。这些数据对开发儿童白血病的靶向治疗具有重要意义。
Evasion of apoptosis may contribute to poor treatment response in pediatric acute lymphoblastic leukemia (ALL), calling for novel treatment strategies. Here, we report that inhibitors of apoptosis (IAPs) at subtoxic concentrations cooperate with various anticancer drugs (that is, AraC, Gemcitabine, Cyclophosphamide, Doxorubicin, Etoposide, Vincristine and Taxol) to induce apoptosis in ALL cells in a synergistic manner as calculated by combination index and to reduce long-term clonogenic survival. Importantly, we identify RIP1 as a critical regulator of this synergism of IAP inhibitors and AraC that mediates the formation of a RIP1/FADD/caspase-8 complex via an autocrine/paracrine loop of tumor necrosis factor-alpha (TNF alpha). Knockdown of RIP1 abolishes formation of this complex and subsequent activation of caspase-8 and -3, mitochondrial perturbations and apoptosis. Similarly, inhibition of RIP1 kinase activity by Necrostatin-1 or blockage of TNF alpha by Enbrel inhibits IAP inhibitor-and AraC-triggered interaction of RIP1, FADD and caspase-8 and apoptosis. In contrast to malignant cells, IAP inhibitors and AraC at equimolar concentrations are non-toxic to normal peripheral blood lymphocytes or mesenchymal stromal cells. Thus, our findings provide first evidence that IAP inhibitors present a promising strategy to prime childhood ALL cells for chemotherapy-induced apoptosis in a RIP1-dependent manner. These data have important implications for developing apoptosis-targeted therapies in childhood leukemia.