MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells

Acta Biochim Biophys Sin (Shanghai). 2012 Aug;44(8):685-91. doi: 10.1093/abbs/gms053.

Abstract

Restoring p53 activity by inhibiting the interaction between p53 and the mouse double minutes clone 2 (MDM2) offers an attractive approach to cancer therapy. Nutlin-3a is a small-molecule inhibitor that inhibits MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. In this study, we determined the efficacy of Nutlin-3a in inducing p53-mediated cell death in osteosarcoma (OS) cell lines both in vivo and in vitro. Targeted disruption of the p53-MDM2 interaction by Nutlin-3a stabilizes p53 and selectively activates the p53 pathway only in OS cells with wild-type p53, resulting in a pronounced anti-proliferative and cytotoxic effect due to G1 cell cycle arrest and apoptosis both in vitro and in vivo. p53 dependence of these alternative outcomes of Nutlin-3a treatment was shown by the abrogation of these effects when p53 was knocked-down by small interfering RNA. These data suggest that the disruption of p53-MDM2 interaction by Nutlin-3a might be beneficial for OS patients with MDM2 amplification and wt p53 status.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Damage
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles / metabolism*
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Osteosarcoma / metabolism*
  • Piperazines / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • RNA, Small Interfering / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Imidazoles
  • Piperazines
  • RNA, Small Interfering
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • nutlin 3
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2