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

De Francesco, EM; Maggiolini, M; Tanowitz, HB; Sotgia, F; Lisanti, MP

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 re-purposed 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.

Citation

implications for optimizing anti-angiogenic therapy. Oncotarget, 2017(8), 56126-56142. https://doi.org/10.18632/oncotarget.18445

• Journal Article Type: Article
• Acceptance Date: May 29, 2017
• Online Publication Date: Jun 12, 2017
• Publication Date: Jun 12, 2017
• Deposit Date: Jul 12, 2017
• Publicly Available Date: Jul 12, 2017
• Journal: Oncotarget
• Publisher: Impact Journals
• Volume: 2017
• Issue: 8
• Pages: 56126-56142
• DOI: https://doi.org/10.18632/oncotarget.18445
• Publisher URL: http://dx.doi.org/10.18632/oncotarget.18445
• Related Public URLs: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=index