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Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells

Yong Tang1, Adly Yacoub, Hossein A Hamed

  • 1Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.

Cancer Biology & Therapy
|March 13, 2012
PubMed

Insights

Sorafenib combined with histone deacetylase inhibitors effectively kills glioblastoma and medulloblastoma cells. This combination therapy targets the extrinsic cell death pathway, offering a potential new treatment for CNS tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioblastoma (GBM) and medulloblastoma are aggressive primary brain tumors.
  • Histone deacetylase inhibitors (HDACi) are emerging cancer therapeutics.
  • Sorafenib is a multi-kinase inhibitor with known anti-cancer activity.

Purpose of the Study:

  • To investigate the synergistic effects of sorafenib and HDAC inhibitors on glioblastoma and medulloblastoma cells.
  • To elucidate the molecular mechanisms underlying the combination therapy's efficacy.

Main Methods:

  • Treatment of human glioblastoma cell lines and medulloblastoma cell lines with sorafenib and HDAC inhibitors (sodium valproate, vorinostat).
  • Assessment of cell viability, phosphorylation of p70 S6K and mTOR.
  • Analysis of apoptosis-related gene expression (CD95, c-FLIP-s, BCL-XL, caspase 9) and PDGFRα.
  • Radio-sensitization assays.

Main Results:

  • Sorafenib and HDAC inhibitors demonstrated dose-dependent lethality in glioblastoma and medulloblastoma cells.
  • The drug combination reduced p70 S6K and mTOR phosphorylation.
  • Knockdown of CD95 or overexpression of c-FLIP-s/BCL-XL/dominant-negative caspase 9 conferred resistance.
  • Knockdown of PDGFRα mimicked the combination's effects.
  • Sorafenib and HDAC inhibitors radio-sensitized both cancer cell types.

Conclusions:

  • Sorafenib in combination with HDAC inhibitors induces cancer cell death via activation of the extrinsic apoptosis pathway.
  • This combination therapy shows promise for treating central nervous system (CNS) tumors like glioblastoma and medulloblastoma.

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