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

// Ernestina Marianna De Francesco 1,2 , Marcello Maggiolini 1 , Herbert B. Tanowitz 3 , Federica Sotgia 4 and Michael P. Lisanti 4 1 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy 2 The Paterson Institute, University of Manchester, Withington, United Kingdom 3 Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA 4 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Manchester, United Kingdom Correspondence to: Michael P. Lisanti, email: // Federica Sotgia, email: // Keywords : anti-oxidant, anti-angiogenic therapy, cancer stem-like cells (CSCs), chronic hypoxia, Doxycycline Received : May 09, 2017 Accepted : May 29, 2017 Published : June 12, 2017 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.