title: Sorafenib inhibits in vitro osteoclastogenesis by down-modulating Mcl-1.
abstract: The effect of the multi-kinase inhibitor Sorafenib was investigated in an in vitro model of human osteoclastogenesis, represented by peripheral blood mononuclear cells (PBMCs) induced to differentiate into osteoclast-like cells in presence of receptor activator of nuclear factor kappa B ligand (RANKL) plus macrophage-colony stimulating factor (M-CSF). Sorafenib significantly inhibited osteoclastic formation at clinically achievable concentrations (1-3 μM) and promoted autophagia with minimal induction of apoptosis. At the molecular levels, the M-CSF + RANKL combination increased the expression level of the Bcl-2 family member Mcl-1 protein, which is known to play a key role in the control of both cell survival and autophagia. The simultaneous treatment with Sorafenib significantly down-regulated endogenous Mcl-1 expression. Conversely, over-expression of Mcl-1 in primary human macrophages significantly counteracted the anti-osteoclastic activity of Sorafenib, strongly suggesting that Mcl-1 down-regulation played a major role in mediating the inhibitory activity of Sorafenib in cells of the osteoclastic lineage.
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Rimondi
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melloni
authors.forename: Vittorio
authors.initials: V
authors.lastname: Grill
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053245:RANK Ligand / Q000494:pharmacology; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D009536:Niacinamide; D016173:Macrophage Colony-Stimulating Factor; D000077157:Sorafenib