title: Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1.
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.
authors.affiliation: Third Department of Medicine, Technical University, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Huber
authors.forename: M
authors.initials: M
authors.lastname: Oelsner
authors.forename: T
authors.initials: T
authors.lastname: Decker
authors.forename: C Meyer
authors.initials: CM
authors.lastname: zum Büschenfelde
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.forename: G
authors.initials: G
authors.lastname: Lutzny
authors.forename: T
authors.initials: T
authors.lastname: Kuhnt
authors.forename: B
authors.initials: B
authors.lastname: Schmidt
authors.forename: R A J
authors.initials: RA
authors.lastname: Oostendorp
authors.forename: C
authors.initials: C
authors.lastname: Peschel
authors.forename: I
authors.initials: I
authors.lastname: Ringshausen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D000077157:Sorafenib; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D034741:RNA, Small Interfering; D009536:Niacinamide; D000077157:Sorafenib; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)