Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells

Marco Fiorillo, Rebecca Lamb, Herbert B. Tanowitz, Luciano Mutti, Marija Krstic-Demonacos, Anna Rita Cappello, Ubaldo E. Martinez-Outschoorn, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Atovaquone is an FDA-approved anti-malarial drug, which first became clinically available in the year 2000. Currently, its main usage is for the treatment of pneumocystis pneumonia (PCP) and/or toxoplasmosis in immune-compromised patients. Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10). It is a well-tolerated drug that does not cause myelo-suppression. Mechanistically, it is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III. Here, we show for the first time that atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that atovaquone treatment of MCF7 breast cancer cells inhibits oxygen-consumption and metabolically induces aerobic glycolysis (the Warburg effect), as well as oxidative stress. Remarkably, atovaquone potently inhibits the propagation of MCF7-derived CSCs, with an IC-50 of 1 μM, as measured using the mammosphere assay. Atovaquone also maintains this selectivity and potency in mixed populations of CSCs and non-CSCs. Importantly, these results indicate that glycolysis itself is not sufficient to maintain the proliferation of CSCs, which is instead strictly dependent on mitochondrial function. In addition to targeting the proliferation of CSCs, atovaquone also induces apoptosis in both CD44+/CD24low/- CSC and ALDH+ CSC populations, during exposure to anchorage-independent conditions for 12 hours. However, it has no effect on oxygen consumption in normal human fibroblasts and, in this cellular context, behaves as an anti-inflammatory, consistent with the fact that it is well-tolerated in patients treated for infections. Future studies in xenograft models and human clinical trials may be warranted, as the IC-50 of atovaquone's action on CSCs (1 μM) is > 50 times less than its average serum concentration in humans.

Original languageEnglish (US)
Pages (from-to)34084-34099
Number of pages16
JournalOncotarget
Volume7
Issue number23
DOIs
StatePublished - Jun 7 2016

Fingerprint

Atovaquone
Neoplastic Stem Cells
Electron Transport Complex III
coenzyme Q10
Glycolysis
Oxygen Consumption
Pneumocystis Pneumonia
Ubiquinone
Toxoplasmosis
Antimalarials
Heterografts
Pharmaceutical Preparations
Population
Oxidative Stress
Anti-Inflammatory Agents
Stem Cells
Fibroblasts
Clinical Trials
Apoptosis
Breast Neoplasms

Keywords

  • Atovaquone
  • Cancer stem-like cells (CSCs)
  • Mitochondria
  • OXPHOS
  • Tumor-initiating cells (TICs)

ASJC Scopus subject areas

  • Oncology

Cite this

Fiorillo, M., Lamb, R., Tanowitz, H. B., Mutti, L., Krstic-Demonacos, M., Cappello, A. R., ... Lisanti, M. P. (2016). Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget, 7(23), 34084-34099. https://doi.org/10.18632/oncotarget.9122

Repurposing atovaquone : Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. / Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B.; Mutti, Luciano; Krstic-Demonacos, Marija; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

In: Oncotarget, Vol. 7, No. 23, 07.06.2016, p. 34084-34099.

Research output: Contribution to journalArticle

Fiorillo, M, Lamb, R, Tanowitz, HB, Mutti, L, Krstic-Demonacos, M, Cappello, AR, Martinez-Outschoorn, UE, Sotgia, F & Lisanti, MP 2016, 'Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells', Oncotarget, vol. 7, no. 23, pp. 34084-34099. https://doi.org/10.18632/oncotarget.9122
Fiorillo M, Lamb R, Tanowitz HB, Mutti L, Krstic-Demonacos M, Cappello AR et al. Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. Oncotarget. 2016 Jun 7;7(23):34084-34099. https://doi.org/10.18632/oncotarget.9122
Fiorillo, Marco ; Lamb, Rebecca ; Tanowitz, Herbert B. ; Mutti, Luciano ; Krstic-Demonacos, Marija ; Cappello, Anna Rita ; Martinez-Outschoorn, Ubaldo E. ; Sotgia, Federica ; Lisanti, Michael P. / Repurposing atovaquone : Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells. In: Oncotarget. 2016 ; Vol. 7, No. 23. pp. 34084-34099.
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