Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Mol Oncol. 2018 Jan;12(1):33-47. doi: 10.1002/1878-0261.12146. Epub 2017 Dec 1.
Acute myeloid leukemia (AML) is an aggressive disease with an increasing incidence and relatively low 5-year survival rate. Unfortunately, the underlying mechanism of leukemogenesis is poorly known, and there has been little progress in the treatment for AML. Studies have shown that X-linked inhibitor of apoptosis (XIAP), one of the inhibitors of apoptosis proteins (IAPs), is highly expressed and contributes to chemoresistance in AML. Hence, a novel drug, RO6867520 (RO-BIR2), developed by Roche targeting the BIR2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML. The monotherapy of RO-BIR2 had minimal effect on most of the AML cell lines tested except U-937. In contrast to AML cell lines, in general, RO-BIR2 alone has been shown to inhibit the proliferation of primary AML patient samples effectively and induced apoptosis in a dose-dependent manner. A combination of RO-BIR2 with TNF-related apoptosis-inducing ligand (TRAIL) led to highly synergistic effect on AML cell lines and AML patient samples. This combination therapy is capable of inducing apoptosis, thereby leading to an increase in specific apoptotic cell population, along with the activation of caspase 3/7. A number of apoptotic-related proteins such as XIAP, cleavage of caspase 3, cleavage of caspase 7, and cleaved PARP were changed upon combination therapy. Combination of RO-BIR2 with Ara-C had similar effect as the TRAIL combination. Ara-C combination also led to synergistic effect on AML cell lines and AML patient samples with low combination indexes (CIs). We conclude that the combination of RO-BIR2 with either TRAIL or Ara-C represents a potent therapeutic strategy for AML and is warranted for further clinical trials to validate the synergistic benefits in patients with AML, especially for the elderly who are abstaining from intensive chemotherapy.
急性髓细胞白血病（AML）是一种侵袭性疾病，发病率不断增加，5 年生存率相对较低。不幸的是，白血病发生的潜在机制尚不清楚，AML 的治疗也几乎没有进展。研究表明，凋亡抑制蛋白（IAPs）之一的 X 连锁凋亡抑制剂（XIAP）在 AML 中高表达并导致化疗耐药。因此，罗氏公司开发的一种新型药物 RO6867520（RO-BIR2）针对 XIAP 的 BIR2 结构域，重新激活被阻断的凋亡，是治疗 AML 的一种很有前途的方法。RO-BIR2 的单药治疗对大多数测试的 AML 细胞系除 U-937 外几乎没有效果。与 AML 细胞系相反，一般来说，RO-BIR2 单独对原代 AML 患者样本的增殖有明显的抑制作用，并呈剂量依赖性诱导凋亡。RO-BIR2 与肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合使用对 AML 细胞系和 AML 患者样本具有高度协同作用。这种联合治疗能够诱导凋亡，从而导致特定凋亡细胞群的增加，同时激活 caspase 3/7。一些凋亡相关蛋白如 XIAP、caspase 3 的切割、caspase 7 的切割和切割的 PARP 在联合治疗后发生改变。RO-BIR2 与 Ara-C 的联合作用与 TRAIL 联合作用相似。Ara-C 联合用药也对 AML 细胞系和 AML 患者样本产生协同作用，联合指数（CI）较低。我们得出结论，RO-BIR2 与 TRAIL 或 Ara-C 的联合使用代表了治疗 AML 的一种有效治疗策略，值得进一步进行临床试验，以验证对 AML 患者的协同获益，特别是对避免强化化疗的老年患者。
