Cytotoxic factors for modulating cell death

Abstract

Cytotoxic factors having use in modulating cell death, and their use in methods of treating necrosis or apoptosis-related conditions are disclosed. The invention also relates to methods for identifying active agents useful in treating conditions related to cell death or uncontrolled growth. The present inventors have found that different microorganisms produce different cytotoxic factor(s) having anticancer activity. The substantially pure cytotoxic factors can be used in a method of treating an infectious disease or a cancer.

1 . A substantially pure protein, that is a mutant and/or truncation of cytochrome c 551 , and promotes growth arrest in cancer cells. 
     
     
         2 . The substantially pure protein of  claim 1 , which comprises an amino acid sequence that is at least about 90% identical with SEQ ID NO: 5. 
     
     
         3 . The substantially pure protein of  claim 1 , that is from the species  Pseudomonas aeruginosa.    
     
     
         4 . The substantially pure protein of  claim 1 , wherein the mutant is a genetically altered form of cytochrome c 551 . 
     
     
         5 . The substantially pure protein of  claim 1 , wherein the protein is chemically modified. 
     
     
         6 . The substantially pure protein of  claim 1 , wherein the cancer cells are selected from the group consisting of melanoma cells, leukemia cells, breast cancer cells, ovarian cancer cells, lung cancer cells, mesenchymal cancer cells, colon cancer cells, and aerodigestive tract cancer cells. 
     
     
         7 . The substantially pure protein of  claim 1 , which is in a pharmaceutically acceptable carrier. 
     
     
         8 . The substantially pure protein of  claim 7 , wherein the pharmaceutically acceptable carrier is suitable for intravenous administration. 
     
     
         9 . The substantially pure protein of  claim 1 , which has low antigenicity. 
     
     
         10 . A therapeutic composition, comprising a one or more substantially pure protein selected from the group consisting of a cupredoxin, cytochrome c 551 , and the substantially pure protein of  claim 1 , in a pharmaceutically acceptable carrier. 
     
     
         11 . The therapeutic composition of  claim 10 , which has low antigenicity. 
     
     
         12 . The therapeutic composition of  claim 10 , wherein the cupredoxin or cytochrome c 551  is from a species selected from the group consisting of  Pseudomonas aeruginosa, Alcaligenes faecalis, Achromobacter xylosoxidans  ssp.  denitrificans, Bordetella bronchiseptica, Methylomonas  sp. J,  Neisseria meningitidis, Pseudomonas fluorescen, Pseudomonas chlorophis, Phormidium laminosum, Thiobacillus ferrooxidans, Achromobacter cycloclastes , and  Xylella fastidiosa.    
     
     
         13 . A method comprising administering to a patient suffering from cancer an effective amount of cytochrome c 551 , or the protein of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the cytochrome c 551  comprises the amino acid sequence of SEQ ID NO: 5. 
     
     
         15 . The method of  claim 13 , wherein the cytochrome c 551  comprises an amino acid sequence having at least about 90% sequence identity with SEQ ID NO: 5. 
     
     
         16 . The method of  claim 13  wherein the cancer is selected from the group consisting of human melanoma, leukemia, breast cancer, ovarian cancer, lung cancer, mesenchymal cancer, colon cancer and aerodigestive tract cancers. 
     
     
         17 . The method of  claim 16  wherein the cancer is breast cancer. 
     
     
         18 . The method of  claim 13 , further comprising administering an effective amount of a cupredoxin selected from a group consisting of an azurin, a pseudoazurin, a plastocyanin, and a rusticyanin.