Benzoquinone derivative e3330 in combination with chemotherapeutic agents for the treatment of cancer and angiogenesis

Abstract

Disclosed are novel methods for the therapeutic treatment of cancer and angiogenesis. The enzyme Ape1/Ref-1, via its redox function, enhances the DNA binding activity of transcription factors that are associated with the progression of cancer. The present invention describes the use of agents to selectively inhibit the redox function of Ape1/Ref-1 and thereby reduce tumor cell growth, survival, migration and metastasis. In addition, Ape1/Ref-1 inhibitory activity is shown to augment the therapeutic effects of other therapeutics and protect normal cells against toxicity. Further, Ape1/Ref-1 inhibition is shown to decrease angiogenesis, for use in the treatment of cancer as well other pathologic conditions of which altered angiogenesis is a component.

What is claimed is: 
     
         1 . A method of treating psoriasis in a subject in need thereof, the method comprising: administering to the subject in need thereof an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid; a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. 
     
     
         2 . The method of  claim 1 , wherein at least one additional therapeutic agent is administered to the subject. 
     
     
         3 . The method of  claim 2 , wherein the additional therapeutic agent is an inhibitor of at least one of Nuclear Factor kappa-light-chain-enhancer of activated B (NFκB) pathway, Signal transducer and activator of transcription 3 (STAT3) pathway, and Hypoxia-inducible factor 1 (HIF-1) pathway. 
     
     
         4 . The method of  claim 1 , wherein the effective amount ranges from about 10 μM to about 100 μM. 
     
     
         5 . A method of treating rheumatoid arthritis in a subject in need thereof, the method comprising: administering to the subject in need thereof an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl 1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid; a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. 
     
     
         6 . The method of  claim 5 , wherein at least one additional therapeutic agent is administered to the subject. 
     
     
         7 . The method of  claim 6 , wherein the additional therapeutic agent is an inhibitor of at least one of Nuclear Factor kappa-light-chain-enhancer of activated B (NFκB) pathway, Signal transducer and activator of transcription 3 (STAT3) pathway, and Hypoxia-inducible factor 1 (HIF-1) pathway. 
     
     
         8 . The method of  claim 5 , wherein the effective amount ranges from about 10 μM to about 100 μM. 
     
     
         9 . A method of treating acute adult respiratory distress syndrome in a subject in need thereof, the method comprising: administering to the subject in need thereof an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid; a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. 
     
     
         10 . The method of  claim 9 , wherein at least one additional therapeutic agent is administered to the subject. 
     
     
         11 . The method of  claim 10 , wherein the additional therapeutic agent is an inhibitor of at least one of Nuclear Factor kappa-light-chain-enhancer of activated B (NFκB) pathway, Signal transducer and activator of transcription 3 (STAT3) pathway, and Hypoxia-inducible factor 1 (HIF-1) pathway. 
     
     
         12 . The method of  claim 9 , wherein the effective amount ranges from about 10 μM to about 100 μM.