In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma

PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013.

Abstract

Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Brain Stem Neoplasms / drug therapy
  • Brain Stem Neoplasms / metabolism*
  • Brain Stem Neoplasms / pathology*
  • Child
  • Child, Preschool
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy
  • Glioma / metabolism*
  • Glioma / pathology*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Neoplasm Grading

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents

Grant support

This work was supported by KiKa “Stichting Kinderen Kankervrij” – Dutch Children Cancer-free foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.