title: Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate.
abstract: CONCLUSIONS
  
  
  
  BACKGROUND
  Cu/Zn superoxide dismutases (SODs) like the extracellular SOD3 and cytoplasmic SOD1 regulate cell proliferation by generating hydrogen peroxide (H2O2). This pro-oxidant inactivates essential cysteine residues in protein tyrosine phosphatases (PTP) helping receptor tyrosine kinase activation by growth factor signaling, and further promoting downstream MEK/ERK linked cell proliferation. Disulfiram (DSF), currently in clinical cancer trials is activated by copper chelation, being potentially capable of diminishing the copper dependent activation of MEK1/2 and SOD1/SOD3 and promoting reactive oxygen species (ROS) toxicity. However, copper (Cu) overload may occur when co-administered with DSF, resulting in toxicity and mutagenicity against normal tissue, through generation of the hydroxyl radical (•OH) by the Fenton reaction.
  
  
  OBJECTIVE
  To investigate: a) whether sub-toxic DSF efficacy can be increased without Cu overload against human melanoma cells with unequal BRAF(V600E) mutant status and Her2-overexpressing SKBR3 breast cancer cells, by increasing H2O2 from exogenous SOD; b) to compare the anti-tumor efficacy of DSF with that of another clinically used copper chelator, tetrathiomolybdate (TTM).
  
  
  RESULTS
  a) without copper supplementation, exogenous SOD potentiated sub-toxic DSF toxicity antagonized by sub-toxic TTM or by the anti-oxidant N-acetylcysteine; b) exogenous glucose oxidase, another H2O2 generator resembled exogenous SOD in potentiating sub-toxic DSF.
  
  
  CONCLUSIONS
  potentiation of sub-lethal DSF toxicity by extracellular H2O2 against the human tumor cell lines investigated, only requires basal Cu and increased ROS production, being unrelated to non-specific or TTM copper chelator sequestration.
  
  
  CONCLUSIONS
  These findings emphasize the relevance of extracellular H2O2 as a novel mechanism to improve disulfiram anticancer effects minimizing copper toxicity.
authors.affiliation: IVIC, Laboratorio de Bioquimica Celular, CMBC, Altos de Pipe, Caracas, Venezuela.
authors.forename: Ali
authors.initials: A
authors.lastname: Calderon-Aparicio
authors.affiliation: IVIC, Laboratorio de Bioquimica Celular, CMBC, Altos de Pipe, Caracas, Venezuela.
authors.forename: Mary
authors.initials: M
authors.lastname: Strasberg-Rieber
authors.affiliation: IVIC, Laboratorio de Bioquimica Celular, CMBC, Altos de Pipe, Caracas, Venezuela.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rieber
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008982:Molybdenum / Q000494:pharmacology*; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology
chemical_list: D000111:Acetylcysteine; D000970:Antineoplastic Agents; D002614:Chelating Agents; D003300:Copper; D004221:Disulfiram; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D008982:Molybdenum; D048493:Proto-Oncogene Proteins B-raf; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D013482:Superoxide Dismutase; C020809:tetrathiomolybdate; C482119:BRAF protein, human
keywords: copper; disulfiram; oxidative stress