Open AccessX‐linked inhibitor of apoptosis inhibition sensitizes acute myeloid leukemia cell response to TRAIL and chemotherapy through potentiated induction of proapoptotic machinery
Author(s) -
Zhou Jianbiao,
Lu Xiao,
Tan Tuan Zea,
Chng WeeJoo
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12146
Subject(s) - xiap , myeloid leukemia , apoptosis , cancer research , inhibitor of apoptosis , combination therapy , cell culture , leukemia , immunology , chemistry , medicine , pharmacology , biology , caspase , programmed cell death , biochemistry , genetics
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 ( IAP s), is highly expressed and contributes to chemoresistance in AML . Hence, a novel drug, RO 6867520 ( RO ‐ BIR 2), developed by Roche targeting the BIR 2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML . The monotherapy of RO ‐ BIR 2 had minimal effect on most of the AML cell lines tested except U‐937. In contrast to AML cell lines, in general, RO ‐ BIR 2 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 ‐ BIR 2 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 ‐ BIR 2 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 ( CI s). We conclude that the combination of RO ‐ BIR 2 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.