Regulation of bioenergetics through dual inhibition of aldehyde dehydrogenase and mitochondrial complex I suppresses glioblastoma tumorspheres

Neuro Oncol. 2018 Jun 18;20(7):954-965. doi: 10.1093/neuonc/nox243.

Abstract

Background: Targeted approaches for treating glioblastoma (GBM) attempted to date have consistently failed, highlighting the imperative for treatment strategies that operate on different mechanistic principles. Bioenergetics deprivation has emerged as an effective therapeutic approach for various tumors. We have previously found that cancer cells preferentially utilize cytosolic NADH supplied by aldehyde dehydrogenase (ALDH) for ATP production through oxidative phosphorylation (OxPhos). This study is aimed at examining therapeutic responses and underlying mechanisms of dual inhibition of ALDH and OxPhos against GBM.

Methods: For inhibition of ALDH and OxPhos, the corresponding inhibitors, gossypol and phenformin were used. Biological functions, including ATP levels, stemness, invasiveness, and viability, were evaluated in GBM tumorspheres (TSs). Gene expression profiles were analyzed using microarray data. In vivo anticancer efficacy was examined in a mouse orthotopic xenograft model.

Results: Combined treatment of GBM TSs with gossypol and phenformin significantly reduced ATP levels, stemness, invasiveness, and cell viability. Consistently, this therapy substantially decreased expression of genes associated with stemness, mesenchymal transition, and invasion in GBM TSs. Supplementation of ATP using malate abrogated these effects, whereas knockdown of ALDH1L1 mimicked them, suggesting that disruption of ALDH-mediated ATP production is a key mechanism of this therapeutic combination. In vivo efficacy confirmed remarkable therapeutic responses to combined treatment with gossypol and phenformin.

Conclusion: Our findings suggest that dual inhibition of tumor bioenergetics is a novel and effective strategy for the treatment of GBM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aldehyde Dehydrogenase / antagonists & inhibitors*
  • Animals
  • Biomarkers, Tumor / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Brain Neoplasms / prevention & control*
  • Cell Proliferation
  • Contraceptive Agents, Male / pharmacology
  • Electron Transport Complex I / antagonists & inhibitors*
  • Energy Metabolism / drug effects*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / prevention & control*
  • Gossypol / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Male
  • Mice
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oxidative Phosphorylation / drug effects*
  • Phenformin / pharmacology
  • Prognosis
  • Survival Rate
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Contraceptive Agents, Male
  • Hypoglycemic Agents
  • Adenosine Triphosphate
  • Phenformin
  • Aldehyde Dehydrogenase
  • Electron Transport Complex I
  • Gossypol