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 reducing angiogenesis 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 the effective amount ranges from about 10 μM to about 100 μM. 
     
     
         3 . The method of  claim 1 , wherein the subject in need thereof has a cancer. 
     
     
         4 . The method of  claim 3 , wherein the cancer is selected from the group consisting of pancreatic cancer, adult and pediatric glioma, prostate cancer, breast cancer, colon cancer, cervical cancer, osteosarcoma, rhabdomyosarcoma, non-small cell lung cancer, leukemia, and multiple myeloma. 
     
     
         5 . The method of  claim 1 , wherein at least one additional therapeutic agent is administered to the subject. 
     
     
         6 . The method of  claim 5 , wherein the additional therapeutic agent is an antibody that specifically binds to Vascular Endothelial Growth Factor. 
     
     
         7 . The method of  claim 1 , wherein the subject in need thereof has advanced macular degeneration (AMD). 
     
     
         8 . A method of inhibiting Vascular Endothelial Growth Factor (VEGF) release 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. 
     
     
         9 . The method of  claim 8 , wherein the effective amount ranges from about 10 μM to about 100 μM. 
     
     
         10 . The method of  claim 8 , wherein the subject in need thereof has a cancer. 
     
     
         11 . The method of  claim 10 , wherein the cancer is selected from the group consisting of pancreatic cancer, adult and pediatric glioma, prostate cancer, breast cancer, colon cancer, cervical cancer, osteosarcoma, rhabdomyosarcoma, non-small cell lung cancer, leukemia, and multiple myeloma. 
     
     
         12 . The method of  claim 8 , wherein at least one additional therapeutic agent is administered to the subject. 
     
     
         13 . The method of  claim 12 , wherein the additional therapeutic agent is an antibody that specifically binds to Vascular Endothelial Growth Factor (VEGF). 
     
     
         14 . The method of  claim 13 , wherein the additional therapeutic agent is bevacizumab. 
     
     
         15 . A method of reducing tubulogenesis 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. 
     
     
         16 . The method of  claim 15 , wherein the effective amount ranges from about 10 μM to about 100 μM. 
     
     
         17 . The method of  claim 15 , wherein the subject in need thereof has a cancer. 
     
     
         18 . The method of  claim 17 , wherein the cancer is selected from the group consisting of pancreatic cancer, adult and pediatric glioma, prostate cancer, breast cancer, colon cancer, cervical cancer, osteosarcoma, rhabdomyosarcoma, non-small cell lung cancer, leukemia, and multiple myeloma. 
     
     
         19 . The method of  claim 15 , wherein the subject in need thereof has advanced macular degeneration (AMD). 
     
     
         20 . The method of  claim 15 , wherein at least one additional therapeutic agent is administered to the subject.