Document Detail


Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1.
MedLine Citation:
PMID:  21293487     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic lymphocytic leukemia (CLL) has a high prevalence in western countries and remains incurable to date. Here, we provide evidence that the multikinase inhibitor sorafenib induces apoptosis in primary CLL cells. This strong pro-apoptotic effect is not restricted to any subgroup of patients, based on Binet stage and the expression of ZAP70 or CD38. Mechanistically, sorafenib-induced cell death is preceded by a rapid downregulation of Mcl-1 through the inhibition of protein translation. Subsequently, the cell intrinsic apoptotic pathway is activated, indicated by destabilization of the mitochondrial membrane potential and activation of caspase-3 and -9. In contrast to sorafenib, the monoclonal vascular epidermal growth factor (VEGF)-antibody bevacizumab failed to induce apoptosis in CLL cells, suggesting that sorafenib induces cell death irrespectively of VEGF signalling. Notably, although sorafenib inhibits phosphorylation of the Scr-kinase Lck, knock-down of Lck did not induce apoptosis in CLL cells. Of note, the pro-apoptotic effect of sorafenib is not restricted to cell-cycle arrested cells, but is also maintained in proliferating CLL cells. In addition, we provide evidence that sorafenib can overcome drug resistance in CLL cells protected by microenvironmental signals from stromal cells. Conclusively, sorafenib is highly active in CLL and may compose a new therapeutic option for patients who relapse after immunochemotherapy.
Authors:
S Huber; M Oelsner; T Decker; C Meyer zum Büschenfelde; M Wagner; G Lutzny; T Kuhnt; B Schmidt; R A J Oostendorp; C Peschel; I Ringshausen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-02-04
Journal Detail:
Title:  Leukemia     Volume:  25     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-11     Completed Date:  2011-08-09     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  838-47     Citation Subset:  IM    
Affiliation:
Third Department of Medicine, Technical University, Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Benzenesulfonates / pharmacology*
Flow Cytometry
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism,  pathology*
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors,  genetics,  metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Pyridines / pharmacology*
RNA, Small Interfering / genetics
Receptors, Platelet-Derived Growth Factor / metabolism
Receptors, Vascular Endothelial Growth Factor / metabolism
Stromal Cells / metabolism
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzenesulfonates; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyridines; 0/RNA, Small Interfering; 0/myeloid cell leukemia sequence 1 protein; 0/sorafenib; EC 2.7.10.1/Receptors, Platelet-Derived Growth Factor; EC 2.7.10.1/Receptors, Vascular Endothelial Growth Factor; EC 2.7.10.2/Lymphocyte Specific Protein Tyrosine Kinase p56(lck)

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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