Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells

• Published in: International journal of molecular sciences 2021-04, Vol.22 (7), p.3711
• Main Authors: Chen, Ssu-Yu, Chang, Yung-Lung, Liu, Shu-Ting, Chen, Gunng-Shinng, Lee, Shiao-Pieng, Huang, Shih-Ming
• Format: Article
• Language: English
• Subjects: Acetaldehyde Dehydrogenase Inhibitors - chemistry; Acetaldehyde Dehydrogenase Inhibitors - pharmacology; Acetaldehyde Dehydrogenase Inhibitors - therapeutic use; Acidification; Alcohol; Aldehyde dehydrogenase; Aldehydes; Angiogenesis; Antioxidants; Apoptosis; Biosynthesis; c-Myc; c-Myc protein; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Cell cycle; Cell death; Cell growth; Cell proliferation; Cell viability; Chemotherapy; copper; Copper - chemistry; Copper - therapeutic use; Copper chloride; Cytotoxicity; Dehydrogenases; Disulfiram; Disulfiram - chemistry; Disulfiram - pharmacology; Disulfiram - therapeutic use; DNA repair; Drug Repositioning; Drug Screening Assays, Antitumor; Enzymatic activity; Enzyme activity; Gene expression; HIF-1α; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Membrane potential; Metabolism; Metabolites; Metastasis; Mitochondria; Mitochondria - drug effects; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; Myc protein; Oral cancer; Oxidation; Oxidative stress; Oxygen consumption; Phosphorylation; Population; Primary Cell Culture; Proteins; Proto-Oncogene Proteins c-myc - metabolism; reactive oxygen species; Senescence; Transcription factors; Tumorigenesis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22073711

Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We explored the potential mechanism behind the cytotoxicity of DSF-Cu /Cu complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu /Cu induced cell death in OECM-1 cells, but not SG cells. DSF-Cu /Cu also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu /Cu in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu /Cu -treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu /Cu induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl increased but DSF- Cu impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu /Cu -treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl complex as a repurposed agent for OSCC cancer therapy.