Disulfiram anti-cancer efficacy without copper overload is enhanced by extracellular H2O2 generation: antagonism by tetrathiomolybdate.

Abstract

HIGHLIGHTS:

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.

PURPOSE:

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.

SIGNIFICANCE:

These findings emphasize the relevance of extracellular H2O2 as a novel mechanism to improve disulfiram anticancer effects minimizing copper toxicity.

• Authors: Ali Calderon-Aparicio, Mary Strasberg-Rieber, Manuel Rieber
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 30 Pg. 29771-81 (Oct 06 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26356671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chelating Agents
• Free Radical Scavengers
• Reactive Oxygen Species
• Copper
• Molybdenum
• tetrathiomolybdate
• Hydrogen Peroxide
• Superoxide Dismutase
• Receptor, ErbB-2
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Disulfiram
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chelating Agents (pharmacology)
• Copper (metabolism)
• Disulfiram (pharmacology)
• Free Radical Scavengers (pharmacology)
• Humans
• Hydrogen Peroxide (metabolism)
• MAP Kinase Signaling System (drug effects)
• Melanoma (genetics, metabolism, pathology)
• Molybdenum (pharmacology)
• Mutation, Missense
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Superoxide Dismutase (pharmacology)