Carfilzomib promotes the osteogenic differentiation potential of mesenchymal stem cells derived from myeloma patients by inhibiting notch1 activity in vitro

Leuk Res. 2014 Aug;38(8):970-6. doi: 10.1016/j.leukres.2014.05.022. Epub 2014 Jun 4.

Abstract

Notch1 signaling plays a key role in the differentiation of mesenchymal stem cells (MSCs). Carfilzomib (CFZ), a second-generation proteasome inhibitor, has potent cytotoxicity against myeloma cells. In this study, we investigated the effects of CFZ on the osteogenic differentiation potential of MSCs derived from myeloma patients (MM-MSCs) in vitro. MM-MSCs showed decreased osteogenic differentiation ability, together with an impairment of notch1 deactivation. The notch1 inhibitor DAPT and the downregulation of notch1 by shRNA promoted osteogenesis in MM-MSCs. Additionally, CFZ treatment resulted in notch1 inhibition and enhanced osteogenesis in MM-MSCs. These findings suggest that CFZ stimulates osteogenesis via notch1 inhibition.

Keywords: Carfilzomib; Mesenchymal stem cells; Multiple myeloma; Notch1; Osteogenic differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Case-Control Studies
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / pathology
  • Mesenchymal Stem Cells / physiology
  • Middle Aged
  • Multiple Myeloma / pathology*
  • Oligopeptides / pharmacology*
  • Osteogenesis / drug effects*
  • Receptor, Notch1 / antagonists & inhibitors*
  • Receptor, Notch1 / metabolism

Substances

  • Antineoplastic Agents
  • NOTCH1 protein, human
  • Oligopeptides
  • Receptor, Notch1
  • carfilzomib