Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1.

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BlankSorafenib induces cell death in chronic lymphocytic leukemia by

translational downregulation of Mcl-1.

Leukemia. 2011 Feb 4;

Authors: Huber S, Oelsner M, Decker T, Zum Büschenfelde CM, Wagner M, Lutzny G,

Kuhnt T, Schmidt B, Oostendorp RA, Peschel C, Ringshausen I

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.Leukemia advance online publication, 4 February 2011;

doi:10.1038/leu.2011.2.

PMID: 21293487 [PubMed - as supplied by publisher]