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 language | English (US) |
|---|---|
| Pages (from-to) | 56126-56142 |
| Number of pages | 17 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 34 |
| DOIs | |
| State | Published - 2017 |
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Keywords
- Anti-angiogenic therapy
- Anti-oxidant
- Cancer stem-like cells (CSCs)
- Chronic hypoxia
- Doxycycline
ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
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.
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 -