Targeting hypoxic cancer stem cells (cscs) with doxycycline: implications for improving anti-angiogenic therapy

Abstract

The present disclosure relates to inhibitors of mitochondrial function. Methods of treating hypoxic cancer cells using anti-angiogenic agents and mitochondrial biogenesis inhibitors are disclosed. Tetracyclines, such as doxycycline, may serve as milochondrial biogenesis inhibitors. Also described are methods of sensitizing hypoxic cancer cells to one or more chemotherapies by administering a milochondrial biogenesis inhibitor with the chemotherapy.

What is claimed is: 
     
         1 . A method of treating hypoxic cancer stem cells (CSCs) comprising administering a therapeutically effective amount of an anti-angiogenic agent and a therapeutically effective amount of a mitochondrial biogenesis inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the anti-angiogenic agent comprises at least one of bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, CM101, INF-alpha, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, a VEGFR antagonist, an angiostatic steroid plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, a matrix metalloproteinase inhibitor, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactin, linomide, αVβ3 inhibitors, ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib and everolimus. 
     
     
         3 . The method of  claim 1 , wherein the mitochondrial biogenesis inhibitor comprises at least one of a tetracycline, doxycycline, tigecycline, minocycline, eyrthromycin, azithromycin, clarithromycin, pyrvinium pamoate, atovaquone, bedaquiline, irinotecan, sorafenib, niclosamide, berberine, stiripentol, chloroquine, etomoxir, perhexiline, mitoriboscin, mitoketoscin, mitoflavoscin, TPP-compound, mDIVI1, caffeic acid phenyl ester, antimitoscin, and repurposcin. 
     
     
         4 . A method of sensitizing hypoxic cancer stem cells CSCs to a chemotherapy, the method comprising: administering a therapeutically effective amount of a mitochondrial biogenesis inhibitor with a chemotherapeutic agent. 
     
     
         5 . The method of  claim 4 , wherein the mitochondrial biogenesis inhibitor comprises at least one of a tetracycline, doxycycline, tigecycline, minocycline, eyrthromycin, azithromycin, clarithromycin, pyrvinium pamoate, atovaquone, bedaquiline, irinotecan, sorafenib, niclosamide, berberine, stiripentol, chloroquine, etomoxir, perhexiline, mitoriboscin, mitoketoscin, mitoflavoscin, TPP-compound, mDIVI1, caffeic acid phenyl ester, antimitoscin, and repurposcin. 
     
     
         6 . The method of  claim 5 , wherein the mitochondrial biogenesis inhibitor is doxycycline. 
     
     
         7 . The method of  claim 4 , wherein the chemotherapeutic agent is paclitaxel. 
     
     
         8 . A compound for treating hypoxic cancer stem cells (CSCs), the compound comprising: an anti-angiogenic agent and a therapeutically effective amount of a mitochondrial biogenesis inhibitor. 
     
     
         9 . The compound of  claim 8 , wherein the anti-angiogenic agent comprises a therapeutically effective amount of at least one of bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, CM101, INF-alpha, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, a VEGFR antagonist, an angiostatic steroid plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, a matrix metalloproteinase inhibitor, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolyhdate, thalidomide, thrombospondin, prolactin, linotnide, αVβ3 inhibitors, ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib, and everolimus. 
     
     
         10 . The compound of  claim 8 , wherein the mitochondrial biogenesis inhibitor comprises a therapeutically effective amount of at least one of a tetracycline, doxycycline, tigecycline, minocycline, eyrthromycin, azithromycin, clarithromycin, pyrvinium pamoate, atovaquone, bedaquiline, irinotecan, sorafenib, niclosamide, berberine, stiripentol, chloroquine, etomoxir, perhexiline, mitoriboscin, mitoketoscin, mitoflavoscin, TPP-compound, mDIVI1, caffeic acid phenyl ester, antimitoscin, and repurposcin. 
     
     
         11 . The compound of  claim 8 , wherein the mitochondrial biogenesis inhibitor comprises a therapeutically effective amount of doxycycline. 
     
     
         12 . A compound for sensitizing hypoxic cancer stem cells (CSCs) to one or more chemotherapies, the compound comprising: a mitochondrial biogenesis inhibitor and a chemotherapeutic agent. 
     
     
         13 . The compound of  claim 12 , wherein the mitochondrial biogenesis inhibitor comprises at least one of a tetracycline, doxycycline, tigecycline, minocycline, eyrthromycin, azithromycin, clarithromycin, pyrvinium pamoate, atovaquone, bedaquiline, irinotecan, sorafenib, niclosamide, berberine, stiripentol, chloroquine, etomoxir, perhexiline, mitoriboscin, mitoketoscin, mitoflavoscin, TPP-compound, mDIVI1, caffeic acid phenyl ester, antimitoscin, and repurposcin. 
     
     
         14 . The compound of  claim 12 , wherein the mitochondrial biogenesis inhibitor is doxycycline. 
     
     
         15 . The compound of  claim 12 , wherein the chemotherapeutic agent comprises paclitaxel. 
     
     
         16 . A method of sensitizing hypoxic cancer stem cells (CSCs) to radiotherapy, the method comprising: administering a therapeutically effective amount of a mitochondrial biogenesis inhibitor with radiotherapy. 
     
     
         17 . The method of  claim 16 , wherein the mitochondrial biogenesis inhibitor comprises at least one of a tetracycline, doxycycline, tigecycline, minocycline, eyrthromycin, azithromycin, clarithromycin, pyryinium pamoate, atovaquone, bedaquiline, irinotecan, sorafenib, niclosamide, berberine, stiripentol, chloroquine, etomoxir, perhexiline, mitoriboscin, mitoketoscin, mitoflavoscin, TPP-compound, mDIVI1, caffeic acid phenyl ester, antimitoscin, and repurposcin. 
     
     
         18 . The method of  claim 16 , wherein the mitochondrial biogenesis inhibitor is doxycycline.