TY - JOUR
T1 - Targeting hypoxic cancer stem cells (CSCs) with Doxycycline
T2 - Implications for optimizing anti-angiogenic therapy
AU - De Francesco, Ernestina Marianna
AU - Maggiolini, Marcello
AU - Tanowitz, Herbert B.
AU - Sotgia, Federica
AU - Lisanti, Michael P.
N1 - Funding Information:
We are grateful to the University of Manchester, which allocated start-up funds and administered a donation, to provide the all the necessary resources required to start and complete this drug discovery project (to MPL and FS). Dr. Ernestina M. De Francesco was supported by a fellowship from the Associazione Italiana per la Ricerca sul Cancro (AIRC) co-funded by the European Union. The Lisanti and Sotgia Laboratories are currently supported by private donations, and by funds from the Healthy Life Foundation (HLF) and the University of Salford (to MPL and FS). We also wish to thank Dr. Duncan Smith, who performed the proteomics analysis on whole cell lysates, within the CRUK Core Facility. MM was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 16719).
Publisher Copyright:
© De Francesco et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Anti-angiogenic therapy
KW - Anti-oxidant
KW - Cancer stem-like cells (CSCs)
KW - Chronic hypoxia
KW - Doxycycline
UR - http://www.scopus.com/inward/record.url?scp=85029070324&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029070324&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.18445
DO - 10.18632/oncotarget.18445
M3 - Article
AN - SCOPUS:85029070324
VL - 8
SP - 56126
EP - 56142
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 34
ER -