Abstract
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+/Cu2+ complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl2 or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu+/Cu2+ induced cell death in OECM-1 cells, but not SG cells. DSF-Cu+/Cu2+ 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+/Cu2+ in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu+/Cu2+-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu+/Cu2+ induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl2 increased but DSF- Cu2+ impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl2 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+/Cu2-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-CuCl2 complex as a repurposed agent for OSCC cancer therapy.
Highlights
Oral squamous cell carcinoma (OSCC) can arise anywhere within the oral cavity, including the buccal mucosa, oral floor, palate, tongue, or upper or lower gingiva [1,2,3]
The DSF-Cu2+ complex failed to inhibit aldehyde dehydrogenase (ALDH) enzyme activity in oral epidermoid carcinoma meng-1 (OECM-1) cells, though it did inhibit the enzyme in SG normal gingival epithelial cells
These findings suggest that the DSF-Cu2+ complex is more effective than the DSF-Cu+ complex when applied as a repurposed agent for treatment of OSCC patients
Summary
Oral squamous cell carcinoma (OSCC) can arise anywhere within the oral cavity, including the buccal mucosa, oral floor, palate, tongue, or upper or lower gingiva [1,2,3]. The oral cavity is richly supplied with lymphatic vessels that form numerous anastomoses, which facilitates cervical lymph node metastasis of late-stage OSCC tumors. The recurrence potential of OSCC is closely associated with nodal metastasis of the tumor. Alcohol consumption promotes a disease state microbiome associated with OSCC [4,5]. The effect of this inflammatory composition is heightened by alcohol-induced modulation of the immune response and cell structures. In response to alcohol consumption, microbes that can contribute to genotoxic levels of acetaldehyde through expression of alcohol dehydrogenase increase reactive oxygen species (ROS) production and promote inflammation. The resulting oral environment, characterized by oxidative stress and inflammation, is susceptible to damage from acetaldehyde and promotes tumorigenesis
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