Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells
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<sup>+</sup>/Cu<sup>2+&l...
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MDPI AG
2021-04-01
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| author | Ssu-Yu Chen Yung-Lung Chang Shu-Ting Liu Gunng-Shinng Chen Shiao-Pieng Lee Shih-Ming Huang |
| author_facet | Ssu-Yu Chen Yung-Lung Chang Shu-Ting Liu Gunng-Shinng Chen Shiao-Pieng Lee Shih-Ming Huang |
| author_sort | Ssu-Yu Chen |
| collection | DOAJ |
| description | 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<sup>+</sup>/Cu<sup>2+</sup> complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl<sub>2</sub> or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu<sup>+</sup>/Cu<sup>2+</sup> induced cell death in OECM-1 cells, but not SG cells. DSF-Cu<sup>+</sup>/Cu<sup>2+</sup> 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<sup>+</sup>/Cu<sup>2+</sup> in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu<sup>+</sup>/Cu<sup>2+</sup>-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu<sup>+</sup>/Cu<sup>2+</sup> induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl<sub>2</sub> increased but DSF- Cu<sup>2+</sup> impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl<sub>2</sub> 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<sup>+</sup>/Cu<sup>2</sup>-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<sub>2</sub> complex as a repurposed agent for OSCC cancer therapy. |
| first_indexed | 2024-03-10T12:39:46Z |
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| language | English |
| last_indexed | 2024-03-10T12:39:46Z |
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| spelling | doaj.art-9330d9dcdaf24eef9ab3beccbc1af21d2023-11-21T14:00:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01227371110.3390/ijms22073711Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer CellsSsu-Yu Chen0Yung-Lung Chang1Shu-Ting Liu2Gunng-Shinng Chen3Shiao-Pieng Lee4Shih-Ming Huang5Department of Biochemistry, National Defense Medical Center, Taipei City 114, TaiwanDepartment of Biochemistry, National Defense Medical Center, Taipei City 114, TaiwanDepartment of Biochemistry, National Defense Medical Center, Taipei City 114, TaiwanSchool of Dentistry, Department of Dentistry of Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, TaiwanSchool of Dentistry, Department of Dentistry of Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, TaiwanDepartment of Biochemistry, National Defense Medical Center, Taipei City 114, TaiwanDisulfiram (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<sup>+</sup>/Cu<sup>2+</sup> complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl<sub>2</sub> or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu<sup>+</sup>/Cu<sup>2+</sup> induced cell death in OECM-1 cells, but not SG cells. DSF-Cu<sup>+</sup>/Cu<sup>2+</sup> 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<sup>+</sup>/Cu<sup>2+</sup> in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu<sup>+</sup>/Cu<sup>2+</sup>-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu<sup>+</sup>/Cu<sup>2+</sup> induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl<sub>2</sub> increased but DSF- Cu<sup>2+</sup> impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl<sub>2</sub> 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<sup>+</sup>/Cu<sup>2</sup>-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<sub>2</sub> complex as a repurposed agent for OSCC cancer therapy.https://www.mdpi.com/1422-0067/22/7/3711disulfiramcopperc-Mycreactive oxygen speciesHIF-1α |
| spellingShingle | Ssu-Yu Chen Yung-Lung Chang Shu-Ting Liu Gunng-Shinng Chen Shiao-Pieng Lee Shih-Ming Huang Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells International Journal of Molecular Sciences disulfiram copper c-Myc reactive oxygen species HIF-1α |
| title | Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells |
| title_full | Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells |
| title_fullStr | Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells |
| title_full_unstemmed | Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells |
| title_short | Differential Cytotoxicity Mechanisms of Copper Complexed with Disulfiram in Oral Cancer Cells |
| title_sort | differential cytotoxicity mechanisms of copper complexed with disulfiram in oral cancer cells |
| topic | disulfiram copper c-Myc reactive oxygen species HIF-1α |
| url | https://www.mdpi.com/1422-0067/22/7/3711 |
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