Loeder Sandra, Zenz Thorsten, Schnaiter Andrea, Mertens Daniel, Winkler Dirk, Döhner Hartmut, Debatin Klaus-Michael, Stilgenbauer Stephan, Fulda Simone
University Children's Hospital, Ulm, Germany.
Cancer Res. 2009 Dec 1;69(23):8977-86. doi: 10.1158/0008-5472.CAN-09-2604. Epub 2009 Nov 17.
Evasion of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL), calling for new strategies to bypass resistance. Here, we provide first evidence that small-molecule X-linked inhibitor of apoptosis (XIAP) inhibitors in combination with the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) present a novel approach to trigger apoptosis in CLL, including subgroups with resistant disease or unfavorable prognosis. XIAP, cellular IAP (cIAP) 1, and cIAP2 are expressed at high levels in primary CLL samples. Proof-of-concept studies in CLL cell lines show that subtoxic concentrations of XIAP inhibitors significantly enhance TRAIL-induced apoptosis and also sensitize for CD95-mediated apoptosis. Importantly also in primary CLL samples, XIAP inhibitor acts in concert with TRAIL to trigger apoptosis in 18 of 27 (67%) cases. This XIAP inhibitor-induced and TRAIL-induced apoptosis involves caspase-3 activation and is blocked by the caspase inhibitor zVAD.fmk. The cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features (i.e., with 17p deletion, TP53 mutation, chemotherapy-refractory disease, or unmutated V(H) genes). Interestingly, cases with unmutated V(H) genes were significantly more sensitive to XIAP inhibitor-induced and TRAIL-induced apoptosis compared with V(H) gene-mutated samples, pointing to a role of B-cell receptor signaling in apoptosis regulation. By showing that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL, our findings have important implications for the development of apoptosis-based therapies in CLL.
逃避凋亡是慢性淋巴细胞白血病（CLL）的一个标志，这就需要新的策略来克服耐药性。在此，我们首次提供证据表明，小分子X连锁凋亡抑制蛋白（XIAP）抑制剂与死亡受体配体肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合使用，是一种在CLL中触发凋亡的新方法，包括对疾病耐药或预后不良的亚组。XIAP、细胞凋亡抑制蛋白（cIAP）1和cIAP2在原发性CLL样本中高表达。在CLL细胞系中进行的概念验证研究表明，亚毒性浓度的XIAP抑制剂可显著增强TRAIL诱导的凋亡，并且还使细胞对CD95介导的凋亡敏感。同样重要的是，在原发性CLL样本中，XIAP抑制剂与TRAIL协同作用，在27例中的18例（67%）中触发凋亡。这种XIAP抑制剂诱导的和TRAIL诱导的凋亡涉及半胱天冬酶-3激活，并被半胱天冬酶抑制剂zVAD.fmk阻断。XIAP抑制剂和TRAIL的协同相互作用在预后不良特征的不同亚组患者中甚至更为明显（即有17p缺失、TP53突变、化疗难治性疾病或未突变的V(H)基因）。有趣的是，与V(H)基因突变样本相比，V(H)基因未突变的病例对XIAP抑制剂诱导的和TRAIL诱导的凋亡明显更敏感，这表明B细胞受体信号在凋亡调节中起作用。通过表明XIAP抑制剂与TRAIL联合使用是一种即使在CLL的耐药形式和预后不良亚组中也能触发凋亡的新策略，我们的发现对基于凋亡的CLL治疗的发展具有重要意义。
