Sorafenib inhibits in vitro osteoclastogenesis by down-modulating Mcl-1

Erika Rimondi, Paola Secchiero, Elisabetta Melloni, Vittorio Grill, Giorgio Zauli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)780-786
Number of pages7
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Autophagia
  • Mcl-1
  • Osteoclasts
  • Sorafenib

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

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    Rimondi, E., Secchiero, P., Melloni, E., Grill, V., & Zauli, G. (2013). Sorafenib inhibits in vitro osteoclastogenesis by down-modulating Mcl-1. Investigational New Drugs, 31(3), 780-786. https://doi.org/10.1007/s10637-012-9903-x