Methods and products related to metabolic interactions in disease

Abstract

The invention involves methods of regulating cell growth and division to control disease processes by manipulating mitochondrial metabolism and the expression of cell surface immune proteins. The invention also involves related compositions and screening assays.

1 . A method for decreasing mitochondrial membrane potential in a mammalian cell, comprising
 administering an MHC class II HLA-DR ligand to the mammalian cell to selectively engage MHC class II HLA-DR on the surface of the cell in an amount effective to decrease mitochondrial membrane potential in the mammalian cell, wherein the mammalian cell is not an antigen presenting cell.   
     
     
         2 . A method for decreasing mitochondrial membrane potential in a mammalian cell, comprising
 contacting the mammalian cell with an amount of an MHC class II HLA-DR inducing agent effective to induce the expression of MHC class II HLA-DR on the surface of the mammalian cell, wherein the mammalian cell is not an antigen presenting cell.   
     
     
         3 . A method for increasing mitochondrial membrane potential in a mammalian cell, comprising
 administering an MHC class II HLA-DP/DQ ligand to the mammalian cell to selectively engage MHC class II HLA-DP/DQ on the surface of the cell in an amount effective to increase mitochondrial membrane potential in the mammalian cell, wherein the mammalian cell is not an antigen presenting cell.   
     
     
         4 . A method for inducing lysis of a mammalian cell, comprising:
 contacting the mammalian cell with an amount of an MHC class II HLA-DR inducing agent effective to induce the expression of MHC class II HLA-DR on the surface of the mammalian cell, and   contacting the MHC class II HLA-DR on the surface of the mammalian cell with an amount of an MHC class II HLA-DR ligand effective for causing lysis of the mammalian cell.   
     
     
         5 . A method for inducing apoptosis in a tumor cell, comprising:
 contacting a tumor cell with an amount of a metabolic modifying agent, which when exposed to a cell causes coupling of electron transport and oxidative phosphorylation, effective to increase the mitochondrial membrane potential in the tumor cell, and   contacting the tumor cell with an amount of an apoptotic chemotherapeutic agent effective for inducing apoptosis in the tumor cell.   
     
     
         6 . The method of  claim 5 , wherein the metabolic modifying agent is a glucose. 
     
     
         7 . The method of  claim 5 , wherein the metabolic modifying agent is an MHC class II HLA-DP/DQ ligand. 
     
     
         8 . The method of  claim 5 , wherein the metabolic modifying agent is selected from the group consisting of phorbol myristate acetate in combination with ionomycin, GDP, CD40 binding peptide, sodium acetate, UCP antisense, dominant negative UCP, and staurosporine. 
     
     
         9 . The method of  claim 5 , wherein the metabolic modifying agent is GDP. 
     
     
         10 . The method of  claim 5 , wherein the apoptotic chemotherapeutic agent is a taxol. 
     
     
         11 . The method of  claim 5 , wherein the metabolic modifying agent and the apoptotic chemotherapeutic agent are administered simultaneously. 
     
     
         12 . The method of  claim 5 , wherein the metabolic modifying agent and the apoptotic chemotherapeutic agent are administered locally. 
     
     
         13 . The method of  claim 11 , wherein the tumor cell is resistant to the apoptotic chemotherapeutic agent. 
     
     
         14 . The method of  claim 5 , wherein the tumor cell is sensitive to the apoptotic chemotherapeutic agent, and wherein the amount of metabolic modifying agent is effective to increase mitochondrial membrane potential and the amount of apoptotic chemotherapeutic agent is effective to inhibit the proliferation of the tumor cell when the mitochondrial membrane potential is increased. 
     
     
         15 . A method for selectively killing a Fas ligand bearing tumor cell, comprising:
 contacting the Fas ligand bearing tumor cell with acetate in an amount effective to induce Fas associated cell death.   
     
     
         16 . A method for screening a tumor cell of a subject for susceptibility to treatment with a chemotherapeutic agent comprising:
 isolating a tumor cell from a subject;   exposing the tumor cell to a chemotherapeutic agent; and,   detecting the presence of a cell death marker selected from the group consisting of a Fas molecule on the surface of the tumor cell, a B7 molecule on the surface of the tumor cell, an MHC class II HLA-DR on the surface of the tumor cell, and a mitochondrial membrane potential indicative of cellular coupling wherein the presence of the cell death marker indicates that the cell is susceptible to treatment with a chemotherapeutic agent.   
     
     
         17 . A method for identifying an anti-tumor drug for killing a tumor cell of a subject comprising:
 isolating a tumor cell from a subject;   detecting the presence of a cell death marker selected from the group consisting of a Fas molecule on the surface of the tumor cell, a B7 molecule on the surface of the tumor cell, an MHC class II HLA-DR on the surface of the tumor cell, and a mitochondrial membrane potential indicative of cellular coupling;   exposing the tumor cell to a putative drug; and,   detecting any change in the presence of the cell death marker to determine whether the putative drug is an anti-tumor drug capable of killing the tumor cell of the subject.   
     
     
         18 . A kit for screening a tumor cell of a subject for susceptibility to treatment with a chemotherapeutic agent comprising:
 a container housing a cell death marker detection reagent; and   instructions for using the cell death marker detection reagent for detecting the presence of a cell death marker selected from the group consisting of a Fas molecule on the surface of the tumor cell, an MHC class II HLA-DR on the surface of the tumor cell, and a mitochondrial membrane potential indicative of cellular coupling wherein the presence of the cell death marker indicates that the cell is susceptible to treatment with a chemotherapeutic agent.   
     
     
         19 . A composition, comprising:
 a metabolic modifying agent; and,   an apoptotic chemotherapeutic agent.   
     
     
         20 . The composition of  claim 19 , wherein the metabolic modifying agent is a glucose. 
     
     
         21 . The composition of  claim 19 , wherein the apoptotic chemotherapeutic agent is a taxol. 
     
     
         22 . The composition of  claim 19 , wherein the metabolic modifying agent and the apoptotic chemotherapeutic agent are present in an amount effective to inhibit the proliferation of a tumor cell. 
     
     
         23 . The composition of  claim 19 , further comprising a pharmaceutically acceptable carrier. 
     
     
         24 . A composition, comprising:
 an MHC class II HLA-DR inducing agent; and,   an MHC class II HLA-DR ligand.   
     
     
         25 . A method for selectively killing a cell, comprising
 contacting the cell with a nucleic acid selected form the group consisting of a UCP anti-sense nucleic acid and a UCP dominant-negative nucleic acid in an amount effect to inhibit UCP function.   
     
     
         26 . A method for selectively killing a tumor cell, comprising:
 contacting the tumor cell with acetate in an amount effective to induce cell surface Fas expression, and   administering a Fas ligand to the tumor cell in an amount effective to induce Fas associated cell death.   
     
     
         27 . A method for selectively killing a tumor cell, comprising:
 contacting the tumor cell with a compound selected from the group consisting of acetate and GDP and an apoptotic chemotherapeutic agent in an amount effective to kill the tumor cell.   
     
     
         28 . A method for treating human breast cancer which contains metabolizing cells, said method comprising the steps of administering to a subject:
 (a) a taxol for killing at least some of the cells; and   (b) a glucose for killing at least some of the cells.   
     
     
         29 . The method of  claim 28 , wherein the glucose is a glucose analog. 
     
     
         30 . The method of  claim 29 , wherein the glucose analog is 2-Deoxy-D-glucose. 
     
     
         31 . A method for treating human breast cancer which contains metabolizing cells, said method comprising the steps of administering to a subject:
 (a) a chemotherapeutic agent for killing at least some of the cells; and   (b) a metabolic modifying agent for killing at least some of the cells.   
     
     
         32 . A method for treating human breast cancer which contains both aerobically and anaerobically metabolizing cells, said method comprising the steps of administering to a patient in need thereof:
 (a) at least one of docataxel and paclitaxel for killing at least some of the aerobically metabolizing cells; and   (b) 2-Deoxy-D-glucose for killing at least some of the anaerobically metabolizing cells.