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  Induction of the mitochondrial permeability transitionUSPTO Application #: 20060166208Title: Induction of the mitochondrial permeability transition Abstract: The present invention relates to process for identifying a compound which induces the mitochondrial permeability transition (MPT) in proliferating cells, wherein said process comprises contacting a cell or cell extract with a compound, determining whether compound binds to adenine nucleotide translocator (ANT), and determining whether the compound selectively induces the MPT in proliferating cells. (end of abstract) Agent: Mcdonnell Boehnen Hulbert & Berghoff LLP - Chicago, IL, US Inventor: Philip John Hogg USPTO Applicaton #: 20060166208 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20060166208. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to modification of mitochondrial membrane permeability in cells and in particular, the identification and use of compounds which selectively induce the MPT in proliferating cells. BACKGROUND OF THE INVENTION [0002] Mitochondria provide ATP to support normal cell function and their perturbation leads to apoptotic and necrotic cell death (Crompton, 1999). An important factor in apoptosis and necrosis is the mitochondrial permeability transition (MPT), which occurs as a result of calcium overload. The cause of the MPT is the opening of a non-specific pore in the inner mitochondrial membrane, known as the mitochondrial permeability transition pore (MPTP) (Crompton et al., 1987). Oxidative stress, adenine nucleotide depletion and elevated inorganic phosphate greatly increase the sensitivity of the pore to calcium concentration. Opening of the MPTP is accompanied by equilibration of all small solutes (<1.5 kD) across the inner mitochondrial membrane. The resultant high protein concentration in the matrix exerts a colloidal osmotic pressure that is responsible for extensive swelling of mitochondria, and ultimately, apoptosis or necrosis. [0003] Adenine nucleotide translocator (ANT) is a 30 kD protein that spans the inner mitochondrial membrane and is central to the MPTP (Crompton et al., 1988). [0004] There is a need to selectively induce the MPT, particularly in proliferating cells, as a means of inducing apoptosis. [0005] The present invention relates to a process for identifying compounds which bind to ANT in mitochondria and selectively induce the MPT in proliferating cells relative to non-proliferating or growth quiescent cells. SUMMARY OF THE INVENTION [0006] According to a first aspect of the invention there is provided a process for identifying a compound which induces the mitochondrial permeability transition (MPT) in proliferating cells, wherein the process comprises contacting a cell or cell extract with a compound, determining whether the compound binds to adenine nucleotide translocator (ANT), and determining whether the compound selectively induces the MPT in proliferating cells. [0007] According to a second aspect of the invention there is provided a process for screening a plurality of compounds to identify a compound which induces MPT in proliferating cells, wherein the process comprises contacting a cell or a cell extract with the plurality of compounds, determining whether any of the compounds bind to ANT, and if so, separately determining for each of the plurality of compounds whether the compound selectively induces the MPT in proliferating cells. [0008] With reference to the first and second aspects of the invention, selective induction of the MPT in proliferating cells may be determined, for example, by comparing the effect of compounds identified as binding to ANT in accordance with the first or second aspect of the invention, on the MPT in proliferating cells with the effect on the MPT in non-proliferating or growth quiescent cells. [0009] Also with reference to the first and second aspects of the invention, in one embodiment the process may involve measuring changes in the cellular concentration of the superoxide (O.sub.2--) anion. In another embodiment, the process may involve measuring changes in Cytochrome C release. [0010] According to a third aspect of the invention there is provided a process for identifying a compound which induces apoptosis in proliferating cells, the process comprising contacting a cell or cell extract with a candidate compound, determining whether there is an increase in cellular superoxide anion (O.sub.2--) concentration, and determining whether the compound selectively induces apoptosis in proliferating cells. [0011] According to a fourth aspect of the invention there is provided a process for identifying a compound which is an inhibitor of angiogenesis, the process comprising contacting a cell or cell extract with a candidate compound, determining whether there is an increase in cellular superoxide anion (O.sub.2--) concentration, and determining whether the compound is an inhibitor of angiogenesis. [0012] According to a fifth aspect of the invention there is provided a method of inducing MPT in a vertebrate, wherein the method comprises administering to the vertebrate a therapeutically effective amount of at least one compound detected in accordance with the process of any one of the first to third aspects of the invention, or a therapeutically effective amount of a pharmaceutical composition comprising at least one of the compounds together with a pharmaceutically acceptable carrier, adjuvant and/or diluent. [0013] According to a sixth aspect of the invention there is provided a method of inducing apoptosis in proliferating mammalian cells, comprising administering to the mammal an apoptosis-inducing amount of a compound identified in accordance with the any one of the first to third aspects of the invention, or a therapeutically effective amount of a pharmaceutical composition comprising at least one of the compounds together with a pharmaceutically acceptable carrier, adjuvant and/or diluent. [0014] According to a seventh aspect of the invention there is provided the use of a compound identified in accordance with any one of the first to third aspects of the invention for the manufacture of a medicament for inducing apoptosis. [0015] According to an eighth aspect of the invention there is provided a method of inhibiting angiogenesis in a mammal, comprising administering to the mammal an angiogenesis-inhibiting amount of a compound identified in accordance with the fourth aspect of the invention, or a therapeutically effective amount of a pharmaceutical composition comprising at least one of the compounds together with a pharmaceutically acceptable carrier, adjuvant and/or diluent. [0016] According to a ninth aspect of the invention there is provided the use of a compound identified in accordance with the fourth aspect of the invention for the manufacture of a medicament for inhibiting angiogenesis. [0017] With reference to any one of the first to ninth aspects of the invention, in one embodiment the compound may be a dithiol reactive compound. [0018] In another embodiment, the compound may have an arsenoxide (or arsenoxide equivalent) moiety. [0019] In a further embodiment, the arsenoxide (or arsenoxide equivalent) compound may have the formula (I): A-[(XBX').sub.nB'--Y].sub.p (I) wherein [0020] A comprises at least one substantially cell-membrane impermeable pendant group; [0021] (XBX').sub.nB' comprises a suitable linker group, where n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; Continue reading... Full patent description for Induction of the mitochondrial permeability transition Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Induction of the mitochondrial permeability transition patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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