Methods and products related to metabolic interactions in disease
First Claim
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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.
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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.
30 Citations
32 Claims
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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.
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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.
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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.
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4. A method for inducing lysis of a mammalian cell, comprising:
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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.
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5. A method for inducing apoptosis in a tumor cell, comprising:
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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. - View Dependent Claims (6, 7, 8, 9, 10, 11, 12, 13, 14)
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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.
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16. A method for screening a tumor cell of a subject for susceptibility to treatment with a chemotherapeutic agent comprising:
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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.
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17. A method for identifying an anti-tumor drug for killing a tumor cell of a subject comprising:
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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.
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18. A kit for screening a tumor cell of a subject for susceptibility to treatment with a chemotherapeutic agent comprising:
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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.
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19. A composition, comprising:
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a metabolic modifying agent; and
,an apoptotic chemotherapeutic agent. - View Dependent Claims (20, 21, 22, 23)
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24. A composition, comprising:
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an MHC class II HLA-DR inducing agent; and
,an MHC class II HLA-DR ligand.
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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.
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26. A method for selectively killing a tumor cell, comprising:
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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.
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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.
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28. A method for treating human breast cancer which contains metabolizing cells, said method comprising the steps of administering to a subject:
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(a) a taxol for killing at least some of the cells; and
(b) a glucose for killing at least some of the cells. - View Dependent Claims (29, 30)
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31. A method for treating human breast cancer which contains metabolizing cells, said method comprising the steps of administering to a subject:
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(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.
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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:
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(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.
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Specification