High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: interaction with IQ motif-containing factors.

Abstract

Triple-negative breast cancer (TNBC) represents an aggressive subtype, for which radiation and chemotherapy are the only options. Here we describe the identification of disulfiram, an FDA-approved drug used to treat alcoholism, as well as the related compound thiram, as the most potent growth inhibitors following high-throughput screens of 3185 compounds against multiple TNBC cell lines. The average IC50 for disulfiram was ~300 nM. Drug affinity responsive target stability (DARTS) analysis identified IQ motif-containing factors IQGAP1 and MYH9 as direct binding targets of disulfiram. Indeed, knockdown of these factors reduced, though did not completely abolish, cell growth. Combination treatment with 4 different drugs commonly used to treat TNBC revealed that disulfiram synergizes most effectively with doxorubicin to inhibit cell growth of TNBC cells. Disulfiram and doxorubicin cooperated to induce cell death as well as cellular senescence, and targeted the ESA(+)/CD24(-/low)/CD44(+) cancer stem cell population. Our results suggest that disulfiram may be repurposed to treat TNBC in combination with doxorubicin.

• Authors: Tyler J W Robinson, Melody Pai, Jeff C Liu, Frederick Vizeacoumar, Thomas Sun, Sean E Egan, Alessandro Datti, Jing Huang, Eldad Zacksenhaus
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 12 Issue 18 Pg. 3013-24 (Sep 15 2013) ISSN: 1551-4005 [Electronic] United States
• PMID: 23974104 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• CD24 Antigen
• Cell Adhesion Molecules
• Epithelial Cell Adhesion Molecule
• Hyaluronan Receptors
• IQ motif containing GTPase activating protein 1
• MYH9 protein, human
• Molecular Motor Proteins
• ras GTPase-Activating Proteins
• Doxorubicin
• Myosin Heavy Chains
• Disulfiram

Topics

• Antigens, Neoplasm (metabolism)
• Antineoplastic Agents (toxicity)
• Apoptosis (drug effects)
• CD24 Antigen (genetics, metabolism)
• Cell Adhesion Molecules (metabolism)
• Cell Line, Tumor
• Cellular Senescence (drug effects)
• Disulfiram (toxicity)
• Doxorubicin (toxicity)
• Drug Synergism
• Epithelial Cell Adhesion Molecule
• Female
• High-Throughput Screening Assays
• Humans
• Hyaluronan Receptors (metabolism)
• MCF-7 Cells
• Molecular Motor Proteins (metabolism)
• Myosin Heavy Chains (metabolism)
• Neoplastic Stem Cells (metabolism)
• Protein Binding
• Triple Negative Breast Neoplasms (metabolism, pathology)
• ras GTPase-Activating Proteins (metabolism)