Compounds, composition, methods, targets for cancer therapy

Abstract

This invention describes methods and pharmaceutical compositions for combinational cancer treatments that are capable of inducing JNK phosphorylation and induce programmed cell death. It also identified genes as target for anti-cancer drug development and enhancement of the chemotherapeutic drug effect for the treatment of cancer. This invention points to a novel method and principle for a new avenue of developing more efficient and low or non cytotoxic cancer treatment.

What is claimed: 
     
         1 . A pharmaceutical compound for treating cancer comprising:
 at least one functional group capable of inhibiting cell trans-plasma membrane electron transport (tPMET), inhibiting cell surface respiration, uncoupling cell surface oxidative phosphorylation, or inhibiting tNOX activity; and   at least one functional group capable of keeping the compound impermeable to cell plasma membrane,   
       wherein 
       the compound does not affect mitochondria respiration in normal cells, 
       the at least one functional group capable of uncoupling cell surface oxidative phosphorylation is selected from the group of oxidative uncouplers consisting of: dinitrophenol (DNP), D5-chloro-3-tert-butyl-2′-chloro-4′-nitrosalicylanilide (S-13), sodium 2,3,4,5,6-pentachlorophenolate (PCP), 4,5,6,7-tetrachloro-2-(trifluoromethyl)-1H-benzimidazole (TTFB), Flufenamic acid (2-[3-(trifluoromethyl)anilino]benzoic acid), 3,5-di-tert-butyl-4-hydroxy-benzylidenemalononitrile (SF6847), carbonyl cyanide m-chloro phenyl hydrazone (CCCP), carbonyl cyanide p-[trifluoromethoxy]-phenyl-hydrazone (FCCP), and alpha-(phenylhydrazono)phenylacetonitrile derivatives, and weak acids comprising comprising the chemical groups selected from the group consisting of weakly acidic phenols, benzimidazoles, N-phenylanthranilates, salicylanilides, phenylhydrazones, salicylic acids, acyldi-thiocarbazates, coumarins, aromatic amines, and cyano group. 
     
     
         2 . The pharmaceutical compound of  claim 1 , wherein the at least one functional group capable of uncoupling cell surface oxidative phosphorylation comprises DNP. 
     
     
         3 . The pharmaceutical compound of  claim 1 , wherein the at least one functional group capable of keeping the compound impermeable to cell plasma membrane is selected from the chemical group consisting of the WST-1/WST-3, WST-4, WST-5, WST-8, WST-9, WST-10, WST-11, XTT, MTS, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The pharmaceutical compound of  claim 1 , wherein the at least one functional group capable of keeping the compound impermeable to cell plasma membrane comprises WST-3 (2-(4-Iodophenyl)-3-(2,4-dinitrophenyl)-5-(2,4-disufophenyl)-2H-tetrazolium). 
     
     
         5 . A pharmaceutical composition for treating cancer comprising:
 a first agent comprising a compound of  claim 1 ; and   a second agent that blocks at least one of HIF, cell hypoxia responses, NF-κB, C1(2 and IKK activities.   
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the second agent comprises a flavonoid. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the second agent comprises apigenin. 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein the second gent comprises an IKK inhibitor, a CK2 inhibitor, a HIF inhibitor, or a tNOX inhibitor. 
     
     
         9 . The pharmaceutical composition of  claim 13 , wherein the IKK inhibitor is selected from the group consisting of BMS-345541, SC-514, IKK-2 Inhibitor IV[5-(p-Fluoropheny0-2-uerido]thiophene-3-carboxamide, IKK Inhibitor VII, IKK Inhibitor II, Wedelolactone, IKK-2 Inhibitor V N-(3,5-Bis-trifluoromethylphenyl)-5-chloro-2-hydrozybenzamide IMD-0354, and IKK-2 Inhibitor VI (5-Phenyl-2-ureido)thiophene-3-carboxamide. 
     
     
         10 . The pharmaceutical composition of  claim 5 , wherein the second agent comprises a pUC19, pcDNA3 (SEQ ID NO: 1 and 3) or siRNA selected from the group consisting of SEQ ID NOs: 10-12. 
     
     
         11 . A pharmaceutical composition for treating cancer in a mammal in thereof comprising:
 a first agent that blocks cell plasma membrane respiration, the first agent being WST-1r (4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzenedisulfonate and 1-methoxy-5-methyl-phanezinium methyl sulfate) or WST-3 (2-(4-Iodophenyl)-3-(2,4-dinitrophenyl)-5-(2,4-disufophenyl)-2H-tetrazolium),   a second agent that blocks at least one of NF-κB, CK2, IKK activities and cell hypoxia responses, and   a pharmaceutically acceptable carrier.   
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein the first agent is WST-1r or WST-3 and the second agent is selected from the group consisting of a flavonoid, apigenin, a NF-κB inhibitor, a HIF inhibitor, a CK2 inhibitor, an IKK inhibitor, a NOX inhibitor, a pUC19, PCDN3 (SEQ ID NO: 1 and 13), siRNAs selected from the group consisting of SEQ ID NOs: 10-12, and siRNAs targeting the expression of the genes selected from the group consisting of SEQ ID NO: 2-5 and 14. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the first agent is WST-1r and the second agent is apigenin. 
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein the first agent is WST-1r and the second agent is IKK inhibitor III. 
     
     
         15 . A method of selectively killing cancer cells comprising contacting a population of cells with a composition of  claim 5  in an amount effective to block the tPMET and/or oxidative phosphorylation and/or the coupling of the tPMET and the oxidative phosphryalation process and inhibiting cancer cell hypoxia responses. 
     
     
         16 . A method of selectively inhibiting cell surface respiration in cancer cells comprising contacting a population of cells with a composition of  claim 11  in an amount effective to block the tPMET and/or oxidative phosphorylation and/or the coupling of the tPMET and the oxidative phosphorylation process.