Targeting hypoxic cancer stem cells (CSCs) with Doxycycline: Implications for optimizing anti-angiogenic therapy

Ernestina Marianna De Francesco, Marcello Maggiolini, Herbert B. Tanowitz, Federica Sotgia, Michael P. Lisanti

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Here, we report new mechanistic insight into how chronic hypoxia increases 'stemness' in cancer cells. Using chemical inhibitors, we provide direct experimental evidence that ROS production and mitochondrial biogenesis are both required for the hypoxia-induced propagation of CSCs. More specifically, we show that hypoxic CSCs can be effectively targeted with i) simple mitochondrial anti-oxidants (Mito-TEMPO) and/or ii) inhibitors of mitochondrial biogenesis (Doxycycline). In this context, we discuss the idea that mitochondrial biogenesis itself may be a primary driver of "stemness" in hypoxic cancer cells, with metabolic links to fatty acid oxidation (FAO). As Doxycycline is an FDA-approved drug, we propose that it could be repurposed to target hypoxic CSCs, either alone or in combination with chemotherapy, i.e., Paclitaxel. For example, we demonstrate that Doxycycline effectively targets the sub-population of hypoxia-induced CSCs that are Paclitaxel-resistant, overcoming hypoxia-induced drug-resistance. Finally, anti-angiogenic therapy often induces tumor hypoxia, allowing CSCs to survive and propagate, ultimately driving tumor progression. Therefore, we suggest that Doxycycline could be used in combination with anti-angiogenic agents, to actively prevent or minimize hypoxia-induced treatment failure. In direct support of this assertion, Paclitaxel is already known to behave as an angiogenesis inhibitor.

Original languageEnglish (US)
Pages (from-to)56126-56142
Number of pages17
JournalOncotarget
Volume8
Issue number34
DOIs
StatePublished - 2017

Fingerprint

Neoplastic Stem Cells
Doxycycline
Organelle Biogenesis
Paclitaxel
Therapeutics
Neoplasms
Angiogenesis Inhibitors
Health Services Needs and Demand
Combination Drug Therapy
Treatment Failure
Drug Resistance
Oxidants
Fatty Acids
Hypoxia
Pharmaceutical Preparations

Keywords

  • Anti-angiogenic therapy
  • Anti-oxidant
  • Cancer stem-like cells (CSCs)
  • Chronic hypoxia
  • Doxycycline

ASJC Scopus subject areas

  • Oncology

Cite this

De Francesco, E. M., Maggiolini, M., Tanowitz, H. B., Sotgia, F., & Lisanti, M. P. (2017). Targeting hypoxic cancer stem cells (CSCs) with Doxycycline: Implications for optimizing anti-angiogenic therapy. Oncotarget, 8(34), 56126-56142. https://doi.org/10.18632/oncotarget.18445

Targeting hypoxic cancer stem cells (CSCs) with Doxycycline : Implications for optimizing anti-angiogenic therapy. / De Francesco, Ernestina Marianna; Maggiolini, Marcello; Tanowitz, Herbert B.; Sotgia, Federica; Lisanti, Michael P.

In: Oncotarget, Vol. 8, No. 34, 2017, p. 56126-56142.

Research output: Contribution to journalArticle

De Francesco, EM, Maggiolini, M, Tanowitz, HB, Sotgia, F & Lisanti, MP 2017, 'Targeting hypoxic cancer stem cells (CSCs) with Doxycycline: Implications for optimizing anti-angiogenic therapy', Oncotarget, vol. 8, no. 34, pp. 56126-56142. https://doi.org/10.18632/oncotarget.18445
De Francesco, Ernestina Marianna ; Maggiolini, Marcello ; Tanowitz, Herbert B. ; Sotgia, Federica ; Lisanti, Michael P. / Targeting hypoxic cancer stem cells (CSCs) with Doxycycline : Implications for optimizing anti-angiogenic therapy. In: Oncotarget. 2017 ; Vol. 8, No. 34. pp. 56126-56142.
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