Prevention and reversal of inflammation induced dna damage

Abstract

Methods of reducing neuronal sensitivity, thereby reducing inflammation and chronic pain, are disclosed herein. Particularly disclosed are methods of administrating the apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, APX3330, to enhance the DNA base excision repair (BER) pathway, thereby reducing neuronal sensitivity to inflammatory mediators and alleviating inflammatory or chronic pain.

1 . A method of reducing neuronal sensitivity in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, which selectively inhibits the amino terminal portion of APE1. 
     
     
         2 . The method as set forth in  claim 1 , wherein the APE1/Ref-1 inhibitor is selected from the group consisting of 3-[(5-(2,3-dimethoxy-6-methyl1,4-benzoquinoyl)]-2-nonyl-2-proprionic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide](APX2009), (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014), pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, and combinations thereof. 
     
     
         3 . The method as set forth in  claim 1 , wherein the APE1/Ref-1 inhibitor is APX3330 and the subject is administered from about 5 μM to about 50 μM APX3330. 
     
     
         4 . The method as set forth in  claim 1  further comprising administering at least one additional therapeutic agent selected from the group consisting of platinum drugs, taxanes, doxorubicin, alkaloids, thalidomide, lenolidomide, pomalidomide, bortexomib, carfilzomib, eribulin, ionizing radiation and combinations thereof to the subject. 
     
     
         5 . (canceled) 
     
     
         6 . A method of treating inflammation and chronic pain in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, which selectively inhibits the amino terminal portion of APE1. 
     
     
         7 . The method as set forth in  claim 6 , wherein the APE1/Ref-1 inhibitor is selected from the group consisting of 3-[(5-(2,3-dimethoxy-6-methyl1,4-benzoquinoyl)]-2-nonyl-2-proprionic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014), pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, and combinations thereof. 
     
     
         8 . The method as set forth in  claim 6 , wherein the APE1/Ref-1 inhibitor is APX3330 and the subject is administered from about 5 μM to about 50 μM APX3330. 
     
     
         9 . The method as set forth in  claim 6  further comprising administering at least one additional therapeutic agent selected from the group consisting of platinum drugs, taxanes, doxorubicin, alkaloids, thalidomide, lenolidomide, pomalidomide, bortexomib, carfilzomib, eribulin, ionizing radiation and combinations thereof to the subject. 
     
     
         10 . (canceled) 
     
     
         11 . The method as set forth in  claim 6 , wherein the subject suffers from at least one of obesity and diabetes. 
     
     
         12 . A method of enhancing neuronal DNA repair function in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, which selectively inhibits the amino terminal portion of APE1. 
     
     
         13 . The method as set forth in  claim 12 , wherein the APE1/Ref-1 inhibitor is selected from the group consisting of 3-[(5-(2,3-dimethoxy-6-methyl1,4-benzoquinoyl)]-2-nonyl-2-proprionic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014), pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, and combinations thereof. 
     
     
         14 . The method as set forth in  claim 12 , wherein the APE1/Ref-1 inhibitor is APX3330 and the subject is administered from about 5 μM to about 50 μM APX3330. 
     
     
         15 . The method as set forth in  claim 12  further comprising administering at least one additional therapeutic agent to the subject. 
     
     
         16 . The method as set forth in  claim 15 , wherein the additional therapeutic agent is selected from the group consisting of platinum drugs, taxanes, doxorubicin, alkaloids, thalidomide, lenolidomide, pomalidomide, bortexomib, carfilzomib, eribulin, ionizing radiation and combinations thereof. 
     
     
         17 . A method of treating chemotherapy-induced peripheral neuropathy (CIPN) in a subject in need thereof, the method comprising administering to the subject an effective amount of an apurinic/apyrimidinic endonuclease 1 redox factor 1 (APE1/Ref-1) inhibitor, pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, which selectively inhibits the amino terminal portion of APE1. 
     
     
         18 . The method as set forth in  claim 17 , wherein the APE1/Ref-1 inhibitor is selected from the group consisting of 3-[(5-(2,3-dimethoxy-6-methyl1,4-benzoquinoyl)]-2-nonyl-2-proprionic acid (APX3330), [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] (APX2009), (2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronapthalen-2-yl)methylidene]-N-methoxypentanamide] (APX2014), pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, and combinations thereof. 
     
     
         19 . The method as set forth in  claim 17  further comprising administering at least one additional therapeutic agent selected from the group consisting of taxanes, doxorubicin, alkaloids, thalidomide, lenolidomide, pomalidomide, bortexomib, carfilzomib, eribulin, ionizing radiation and combinations thereof to the subject. 
     
     
         20 . The method as set forth in  claim 19 , wherein the at least one additional therapeutic agent is selected from the group consisting of docetaxel, cabazitaxel, doxorubicin, vincristine, etoposide thalidomide, lenolidomide, pomalidomide, bortexomib, carfilzomib, eribulin, and ionizing radiation. 
     
     
         21 . The method as set forth in  claim 17 , wherein the APE1/Ref-1 inhibitor is APX3330 and the subject is administered from about 5 μM to about 50 μM APX3330.