Repurposing FDA approved drugs inhibiting mitochondrial function for targeting glioma-stem like cells

Biomed Pharmacother. 2021 Jan;133:111058. doi: 10.1016/j.biopha.2020.111058. Epub 2020 Dec 8.

Abstract

Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 μM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.

Keywords: Antimycin A (CID: 6604296); Cancer stem cells; Chemotherapy; Drug repurposing; Glioblastoma multiforme; Mitochondria; Mitoxantrone (CID:4212); Oligomycin A (CID: 5281899); Pyrvinium pamoate (CID:54680693); Rotenone (CID:6758); Therapeutics; Trifluoperazine (CID:5566).

Publication types

  • Comparative Study

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Repositioning*
  • Gene Expression Regulation, Neoplastic
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents