Na/K-ATPase Ligands, Ouabain Antagonists, Assays and Uses Thereof

Abstract

The present disclosure relates to methods of inhibiting the ATPase activity of Na/K-ATPase without stimulating the receptor function, methods of blocking Na/K-ATPase interaction with Src, methods of inhibiting cell growth, and methods of abolishing ouabain-provoked signaling transduction in the heart of a subject, which includes providing an effective amount of at least one hydroxyl xanthone derivative.

What is claimed is: 
     
         1 . A method for inhibiting the ATPase activity without stimulating the receptor function of Na/K-ATPase in a cell in need thereof, comprising:
 administering an effective amount of at least one Na/K-ATPase ligand comprising at least one hydroxyl xanthone derivative having the structure:   
       
         
           
           
               
               
           
         
         wherein one or more of R1, R3, R4, R5 and R6 are selected from H, OH, OCH 3 , carboxylic acid ester, or analog thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the Na/K-ATPase ligand is present in an amount ranging from about 40 pM to about 50 μM. 
     
     
         3 . The method of  claim 1 , wherein the Na/K-ATPase ligand is selected from the group consisting of: MB1 (1,3-dihydroxyxanthone); MB2 (3,4-dihydroxyxanthone); MB3 (1,3,5-trihydroxyxanthone); MB5 (3,4,5-trihydroxyxanthone); MB6 (1,3,5,6-tetrahydroxyxanthone); and MB7 (3,4,5,6- tetrahydroxyxanthone). 
     
     
         4 . The method of  claim 1 , wherein the Na/K-ATPase ligand comprises MB5 (3,4,5-trihydroxyxanthone) and the effective amount ranges from about 40 pM to about 50 μM. 
     
     
         5 . The method of  claim 1 , wherein the Na/K-ATPase ligand comprises MB7 (3,4,5,6-tetrahydroxyxanthone) and the effective amount ranges from about 40 μM to about 50 μM. 
     
     
         6 . The method of  claim 1 , further comprising inhibiting the ATPase activity in a subject having or at risk for having cardiac hypertrophy, tissue fibrosis, cancer, and/or congestive heart failure. 
     
     
         7 . The method of  claims 1 , wherein the hydroxyl xanthone derivative is administered in an amount effective for targeting the Na/K-ATPase-interacting pool of Src and acting as a cardiotonic steroid (CTS) antagonist in one or more cells in need thereof. 
     
     
         8 . The method of  claim 1 , wherein the hydroxyl xanthone derivative is administered in an amount effective for inducing cell growth inhibition and/or cell death in a subject in need. 
     
     
         9 . A method of  claim 8 , further comprising inducing cell growth inhibition and/or cell death in a subject having or at risk for cancer. 
     
     
         10 . The method of  claim 1 , wherein the hydroxyl xanthone derivative is administered in an amount effective for preventing or ameliorating the symptoms of cardiovascular diseases and cancer wherein the Na/K-ATPase/Src receptor is overstimulated. 
     
     
         11 . The method of  claim 1 , wherein the hydroxyl xanthone derivative is administered in an amount effective for preventing CTS-provoked signaling pathway in a subject in need thereof. 
     
     
         12 . The method of  claim 11 , wherein the CTS is ouabain. 
     
     
         13 . The method of  claim 11 , further comprising preventing CTS-provoked signaling pathway in the heart of the subject. 
     
     
         14 . The method of  claim 11 , further comprising preventing CTS-provoked signaling pathway in a subject having or at risk for having cardiac hypertrophy, tissue fibrosis, and/or congestive heart failure. 
     
     
         15 . A method for inhibiting the ATPase activity without stimulating the receptor function of Na/K-ATPase in a cell in need thereof, comprising:
 administering an effective amount of mitomycin or 4-epitetracycline.