Modulators of the ABC Transporter Family and Methods for Their Use

Abstract

An isolated factor derived from the bacterium Pseudomonas aeruginosa and confirmed by proteomics to be a protein that reduces expression of ABC transmembrane proteins and active fragments and mimetics thereof are provided. Also provided is a method for inhibiting expression of ABC transmembrane proteins in cells by administering to the cells the isolated factor or protein or active fragment thereof or a mimetic thereof. Such methods are useful in the enhancing delivery of small molecule therapeutic agents to the CNS and in treating cancers, particularly multidrug resistant cancers, and secretory diarrhea. In addition, compositions, methods for identifying compositions and methods for use of compositions that inhibit suppression of ABC transmembrane protein expression or reduce epoxide hydrolase activity by this factor are provided. Such compositions and methods are useful in treatment of cystic fibrosis.

1 . A composition that modulates plasma membrane expression of ABC transmembrane comprising a Cif protein of SEQ ID NO:1 or an active fragment thereof or a mimetic thereof and a physiologically acceptable vehicle. 
     
     
         2 . The composition of  claim 1  formulated for intravenous administration. 
     
     
         3 . The composition of  claim 1  formulated for oral administration. 
     
     
         4 . A method for modulating plasma membrane expression of an ABC transmembrane protein in a cell comprising administering to the cell the composition of  claim 1 . 
     
     
         5 . A method for delivering a small molecule therapeutic agent to the central nervous system of a subject comprising:
 (a) administering to the subject the composition of  claim 1  so that expression of an ABC transmembrane protein which prevents small molecules from entering into or accumulating in the central nervous system is inhibited in the subject; and   (b) administering to the subject the small molecule therapeutic agent.   
     
     
         6 . A method for treating cancer in a subject comprising:
 (a) administering to the subject the composition of  claim 1  so that expression of an ABC transmembrane protein which confers drug resistance in cancer cells is inhibited in the subject; and   (b) administering to the subject an anti-cancer agent.   
     
     
         7 . The method of  claim 6  wherein the cancer is resistant to therapy due to overexpression of ABC transmembrane proteins. 
     
     
         8 . The method of  claim 6  wherein the cancer comprises a cancer of the central nervous system. 
     
     
         9 . A method for treating secretory diarrhea in a subject comprising administering to the subject the composition of  claim 1  so that plasma membrane expression of intestinal CFTR is reduced and massive fluid and electrolyte losses in secretory diarrhea is inhibited. 
     
     
         10 . A composition comprising an agent which inhibits suppression of plasma membrane expression of ABC transmembrane proteins by the Cif protein of SEQ ID NO:1 or active fragment thereof. 
     
     
         11 . The composition of  claim 10  wherein the agent inhibits suppression of apical expression of CFTR. 
     
     
         12 . A method for inhibiting suppression of CFTR expression in cells infected by  Pseudomonas aeruginosa , said method comprising administering to the cells the composition of  claim 11 . 
     
     
         13 . The method of  claim 12  wherein the cells are in a subject. 
     
     
         14 . A method for treating or alleviating symptoms of a subject suffering from cystic fibrosis comprising administering to the subject the composition of  claim 11 . 
     
     
         15 . The method of  claim 14  further comprising administering to the subject a therapy which promotes CFTR exit from an endoplasmic reticulum, activates CFTR in an apical plasma membrane, or increases half-life of CFTR in an apical membrane. 
     
     
         16 . The method of  claim 14  further comprising administering to the subject an agent which increases apical membrane expression of ΔF508. 
     
     
         17 . The method of  claim 14  further comprising administering to the subject an anti-pseudomonas regimen of antibiotics. 
     
     
         18 . A method for identifying an agent for treatment or alleviation of symptoms of cystic fibrosis comprising assessing a test agent's ability to inhibit suppression of CFTR expression by the Cif protein of SEQ ID NO:1 or an active fragment thereof, wherein the ability of the test agent to inhibit suppression of CFTR expression by the Cif protein or active fragment thereof is indicative of the agent being useful for treatment or alleviation of symptoms of cystic fibrosis. 
     
     
         19 . A method for identifying an agent for reducing or eliminating the epoxide hydrolase activity of the Cif protein of SEQ ID NO:1 or an active fragment thereof, wherein the ability of the test agent to inhibit epoxide hydrolase activity by the Cif protein or active fragment thereof is indicative of the agent being useful for treatment or alleviation of symptoms of cystic fibrosis. 
     
     
         20 . A method for increasing bioavailability of an orally administered therapeutic agent, said method comprising orally administering to a subject a composition of  claim 1  before, simultaneously or after oral administration of the therapeutic agent to the subject. 
     
     
         21 . A formulation of a therapeutic agent with increased oral bioavailability, said formulation comprising the therapeutic agent and a composition of  claim 1 .