X‐linked inhibitor of apoptosis inhibition sensitizes acute myeloid leukemia cell response to TRAIL and chemotherapy through potentiated induction of proapoptotic machinery

Abstract

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.

A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase

“…The unlimited proliferation and evasion of apoptosis as well as differentiation arrested are characteristic of AML cells [ 33 , 34 ]. Deregulated signal transduction pathways, resulting from multiple genetic or epigenetic lesions, are believed to be the fundamental causes of the leukemogenesis [ 35 – 37 ].…”

ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia

“…Experiments were conducted as previously described. 20 , 21 Details of the cell viability assays, western blot analysis, realtime quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and FACS analysis of myeloid cell surface antigens are available in the Online Supplementary Methods . The primer sequences are provided in Online Supplementary Table S1 .…”

“…Experiments were conducted as previously described. 20,21 Details are available in the Supplemental Methods (Haematologica Web site). The primer sequences were provided in the Supplemental Table S1.…”

Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism

“…Small-molecule inhibitors of more recent identification, such as RO-BIR2, may circumvent this drawback, eliciting a rapid and durable inhibition of their IAP targets. In fact, this XIAP inhibitor developed by the Roche Co. (Basel, Switzerland) targets the BIR2 domain, involved in multiple molecular contacts with caspase-3 and -7: these caspases are released, following treatment with RO-BIR2, and induce PARP activation and apoptosis [307]. RO-BIR2 clearly synergize with TRAIL or with Ara-C in inducing cell death of primary AML cells, supporting phase I clinical studies evaluating these drug associations [307].…”