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Chronic Lymphocytic Leukemia

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

Leukemia volume 25, pages 838–847 (2011)Cite this article

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Abstract

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.

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Acknowledgements

SH, TD, CMzB and CP provided experimental concept and planned experiments. MO, MW, TK and GL performed experiments and analyzed data. CLL/co-culturing experiments were done in collaboration with RO and BS. IR wrote the paper, analyzed data and provided experimental concept. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB TRR 54 TP C03) to IR and (DFG ME 1913/3-1) to CMzB and (DFG OO8/5-1 and OO8/2-3) to RO.

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  1. S Huber and M Oelsner: These authors contributed equally to this work.

Authors and Affiliations

  1. Third Department of Medicine, Technical University, Munich, Germany

    S Huber, M Oelsner, T Decker, C Meyer zum Büschenfelde, M Wagner, G Lutzny, T Kuhnt, R A J Oostendorp, C Peschel & I Ringshausen

  2. Onkologie Ravensburg, Ravensburg, Germany

    T Decker

  3. Hämatologie-Onkologie Pasing, Munich, Germany

    B Schmidt

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Correspondence to I Ringshausen.

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Huber, S., Oelsner, M., Decker, T. et al. Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1. Leukemia 25, 838–847 (2011). https://doi.org/10.1038/leu.2011.2

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