The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

Cancers

Marianne van Dijk²  Eoin Murphy²  Ruth Morrell²  Steven Knapper¹  Michael Oɽwyer²  Afshin Samali² 

[1] Department of Haematology, School of Medicine, Cardiff University, Heath Park, CF14 4XN Cardiff, UK; E-Mail:;Apoptosis Research Center, National University of Ireland, University Road, Galway, Ireland; E-Mails:

关键词: AML;    FAB M4/M5;    TRAIL;    bortezomib;    apoptosis;    NF-κB;    c-FLIP;   

DOI  :  10.3390/cancers3011329

来源: mdpi

【 摘 要 】

Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.