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Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma

Li R Kong1, Tuan Z Tan1, Weijie R Ong2

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Molecular Oncology
|April 12, 2017
PubMed

Insights

Belinostat, a histone deacetylase inhibitor, shows promise for lung squamous cell carcinoma (SCC) treatment by downregulating the MAPK pathway and inducing apoptosis. Combination therapy with cisplatin demonstrates synergistic cytotoxicity in preclinical models.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Personalized therapy advances in lung adenocarcinoma contrast with limited options for lung squamous cell carcinoma (SCC).
  • Lack of actionable driver oncogenes in SCC hinders targeted small-molecule inhibitor development.
  • Histone deacetylase inhibitors represent a potential therapeutic avenue for SCC.

Purpose of the Study:

  • To investigate the efficacy and mechanism of belinostat in lung squamous cell carcinoma (SCC).
  • To explore the potential of belinostat in combination with cisplatin for chemoresistant SCC.

Main Methods:

  • Differential sensitivity screening of SCC cell lines with belinostat.
  • Phosphoproteomic analysis of belinostat-treated SCC cells.
  • Assessment of synergistic cytotoxicity and molecular pathway modulation in combination therapy.

Main Results:

  • Belinostat treatment downregulated the MAPK pathway and induced apoptosis in SCC cells.
  • Combined belinostat and cisplatin synergistically reduced cisplatin-resistant SCC cell viability by inhibiting ERK phosphorylation.
  • Belinostat upregulated FBXO3 and FBXW10, leading to proteasomal degradation of SOS and MAPK pathway suppression.

Conclusions:

  • Belinostat exhibits epigenetic cytotoxicity in SCC by targeting the MAPK pathway via F-box protein induction.
  • Combination therapy with belinostat and cisplatin shows potential for treating chemorefractory SCC.
  • These findings support belinostat as a therapeutic agent for SCC, particularly in combination regimens.
Keywords:
MAPK inhibitionhistone deacetylase inhibitorslung squamous cell carcinomaubiquitin-proteasome system

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