Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors

Neuro Oncol. 2015 Jun;17(6):810-21. doi: 10.1093/neuonc/nou305. Epub 2014 Nov 4.

Abstract

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are among the most malignant pediatric brain tumors. Cells from brain tumors with high aldehyde dehydrogenase (ALDH) activity have a number of characteristics that are similar to brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT.

Methods: Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. The therapeutic effect of DSF against BTICs from AT/RT was confirmed in vitro and in vivo.

Results: AT/RT cells displayed a high expression of ALDH. DSF demonstrated a more potent cytotoxic effect on ALDH(+) AT/RT cells compared with standard anticancer agents. Notably, treatment with DSF did not have a considerable effect on normal neural stem cells or fibroblasts. DSF significantly inhibited the ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, and proliferation potential and induced apoptosis and cell cycle arrest in ALDH(+) AT/RT cells. Importantly, DSF reduced the metabolism of ALDH(+) AT/RT cells by increasing the nicotinamide adenine dinucleotide ratio of NAD(+)/NADH and regulating Silent mating type Information Regulator 2 homolog 1 (SIRT1), nuclear factor-kappaB, Lin28A/B, and miRNA let-7g. Animals in the DSF-treated group demonstrated a reduction of tumor volume (P < .05) and a significant survival benefit (P = .02).

Conclusion: Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application.

Keywords: aldehyde dehydrogenase; atypical teratoid/rhabdoid tumors; brain tumor initiating cells; disulfiram; sirtuin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaldehyde Dehydrogenase Inhibitors / administration & dosage*
  • Acetaldehyde Dehydrogenase Inhibitors / therapeutic use
  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / physiopathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Survival / drug effects
  • Disulfiram / administration & dosage*
  • Disulfiram / therapeutic use
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / physiology
  • Rhabdoid Tumor / drug therapy
  • Rhabdoid Tumor / metabolism*
  • Rhabdoid Tumor / physiopathology
  • Signal Transduction / drug effects
  • Teratoma / drug therapy
  • Teratoma / metabolism*
  • Teratoma / physiopathology
  • Tumor Cells, Cultured

Substances

  • Acetaldehyde Dehydrogenase Inhibitors
  • Antineoplastic Agents
  • Aldehyde Dehydrogenase
  • Disulfiram

Supplementary concepts

  • Teratoid Tumor, Atypical