Inhibition of elongation factor-2 kinase augments the antitumor activity of Temozolomide against glioma

PLoS One. 2013 Nov 26;8(11):e81345. doi: 10.1371/journal.pone.0081345. eCollection 2013.

Abstract

Background: Glioblastoma multiforme (GBM), the most common form of brain cancer with an average survival of less than 12 months, is a highly aggressive and fatal disease characterized by survival of glioma cells following initial treatment, invasion through the brain parenchyma and destruction of normal brain tissues, and ultimately resistance to current treatments. Temozolomide (TMZ) is commonly used chemotherapy for treatment of primary and recurrent high-grade gliomas. Nevertheless, the therapeutic outcome of TMZ is often unsatisfactory. In this study, we sought to determine whether eEF-2 kinase affected the sensitivity of glioma cells to treatment with TMZ.

Methodology/principal findings: Using RNA interference approach, a small molecule inhibitor of eEF-2 kinase, and in vitro and in vivo glioma models, we observed that inhibition of eEF-2 kinase could enhance sensitivity of glioma cells to TMZ, and that this sensitizing effect was associated with blockade of autophagy and augmentation of apoptosis caused by TMZ.

Conclusions/significance: These findings demonstrated that targeting eEF-2 kinase can enhance the anti-glioma activity of TMZ, and inhibitors of this kinase may be exploited as chemo-sensitizers for TMZ in treatment of malignant glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Elongation Factor 2 Kinase / antagonists & inhibitors
  • Elongation Factor 2 Kinase / genetics*
  • Glioma / drug therapy
  • Glioma / genetics*
  • Glioma / mortality
  • Glioma / pathology
  • Humans
  • Male
  • Mice
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • Temozolomide
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • Protein Kinase Inhibitors
  • Dacarbazine
  • Elongation Factor 2 Kinase
  • Temozolomide

Grant support

This project was supported by the National Natural Sciences Foundation of China (81072146; 81101913), Natural Science Foundation of Jiangsu Province of China (BK2010224), Natural Science Foundation of Jiangsu provincial Colleges and Universities (12KJD310005), Science and Technology Foundation of Suzhou City (SYS201319), and by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.