Targeting of EGFR increase anti-cancer effects of arsenic trioxide: Promising treatment for glioblastoma multiform

Eur J Pharmacol. 2018 Feb 5;820:274-285. doi: 10.1016/j.ejphar.2017.12.041. Epub 2017 Dec 20.


Glioblastoma multiform (GBM) accounts for the most common form of primary brain tumors with very limited survival rate. Drug resistance is the main challenges for good prognosis of GBM patients. Arsenic trioxide (ATO) as a multifunctional drug has been investigated for the treatment of several solid tumors. Amplification/overexpression of the epidermal growth factor receptor (EGFR) gene as a signature genetic abnormality of GBM tumors can be a chemoresistance mechanism. In this study, we use erlotinib as an EGFR inhibitor to increase the sensitivity of GBM cell lines to ATO treatment. We evaluate the effects of this combination on metabolic activity, viability, cell proliferation, colony formation, cell cycle distribution, migration, oxidative stress and reactive oxygen species production. Our results showed that combination of ATO with erlotinib synergistically reduced metabolic activity, proliferation and colony forming potential in treated GBM cell lines. This combination induced G2/M cell cycle arrest. We also found that wound-healing rate were suppressed only after combination treatment. In addition, apoptotic cell death and reactive oxygen species content significantly increased after combination treatment. The combination of ATO and erlotinib considerably interfere with survival and migration of treated GBM cell lines through cell cycle arrest and reactive oxygen species production. Present study uncovered that EGFR inhibition could overcome the resistance of glioblastoma cells to ATO treatment.

Keywords: Arsenic trioxide; EGFR-targeted therapy; Epidermal growth factor receptor; Glioblastoma; Therapeutic resistance.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Arsenicals / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Synergism
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride / pharmacology
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • M Phase Cell Cycle Checkpoints / drug effects
  • Molecular Targeted Therapy*
  • Oxides / pharmacology*
  • Oxides / therapeutic use
  • Reactive Oxygen Species / metabolism


  • Antineoplastic Agents
  • Arsenicals
  • Oxides
  • Reactive Oxygen Species
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Arsenic Trioxide