| Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbation in NF-κB and Bim. | |
| | |
MedLine Citation:
|
PMID: 21375523 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
Interactions between the histone deacetylase inhibitor belinostat and the proteasome inhibitor bortezomib were investigated in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) cells. Co-administration of sub-micromolar concentrations of belinostat with low nanomolar concentrations of bortezomib sharply increased apoptosis in both AML and ALL cell lines and primary blasts. Synergistic interactions were associated with interruption of both canonical and non-canonical nuclear factor (NF)-κB signalling pathways, e.g. accumulation of the phosphorylated (S32/S36) form of IκBα, diminished belinostat-mediated RelA/p65 hyperacetylation (K310), and reduced processing of p100 into p52. These events were accompanied by down-regulation of NF-κB-dependent pro-survival proteins (e.g. XIAP, Bcl-xL). Moreover, belinostat/bortezomib co-exposure induced up-regulation of the BH3-only pro-death protein Bim. Significantly, shRNA knock-down of Bim substantially reduced the lethality of belinostat/bortezomib regimens. Administration of belinostat ± bortezomib also induced hyperacetylation (K40) of α-tubulin, indicating histone deacetylase inhibitor 6 inhibition. Finally, in contrast to the pronounced lethality of belinostat/bortezomib toward primary leukaemia blasts, equivalent treatment was relatively non-toxic to normal CD34(+) cells. Together, these findings indicate that belinostat and bortezomib interact synergistically in both cultured and primary AML and ALL cells, and raise the possibilities that up-regulation of Bim and interference with NF-κB pathways contribute to this phenomenon. They also suggest that combined belinostat/bortezomib regimens warrant further attention in acute leukaemias. |
| | |
Authors:
|
Yun Dai; Shuang Chen; Li Wang; Xin-Yan Pei; Lora B Kramer; Paul Dent; Steven Grant |
Related Documents
:
|
16978533 - The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. 19423693 - Functional taut protects against acute kidney injury. 9633803 - Differential effects of central and peripheral nerves on macrophages and microglia. |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2011-3-6 |
Journal Detail:
|
Title: British journal of haematology Volume: - ISSN: 1365-2141 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
|
Created Date: 2011-3-7 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0372544 Medline TA: Br J Haematol Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
|
© 2011 Blackwell Publishing Ltd. |
Affiliation:
|
Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center Departments of Biochemistry, and Human and Molecular Genetics, Virginia Commonwealth University and the Massey Cancer Center and Institute of Molecular Medicine Virginia Commonwealth University Health Sciences Center, Richmond, VA, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with...
Next Document: Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma.