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http://dx.doi.org/10.14405/kjvr.2019.59.4.195

Anti-tumor activity and mitochondrial stability of disulfiram in HL-60 cells  

Shin, Hyowon (Veterinary Medical Research Institute, College of Veterinary Medicine, Jeju National University)
Han, Yong (Veterinary Medical Research Institute, College of Veterinary Medicine, Jeju National University)
Joo, Hong-Gu (Veterinary Medical Research Institute, College of Veterinary Medicine, Jeju National University)
Publication Information
Korean Journal of Veterinary Research / v.59, no.4, 2019 , pp. 195-199 More about this Journal
Abstract
Disulfiram (DSF) is a member of the dithiocarbamate family that can bind copper. Recent studies have shown that DSF has anti-cancer activities, but the mechanism has not been clarified. Therefore, it is important to study the action mechanism of DSF to maximize its anticancer effects. A human leukemia cell line, HL-60, was used in this study. HL-60 cells were treated with DSF and the cellular metabolic activity was measured. DSF increased the cell death of HL-60 cells in annexin V-fluorescein isothiocyanate/propidium iodide staining analysis. In addition, DSF decreased the mitochondrial membrane potential (MMP) of the HL-60 cells. The cytotoxicity of DSF on HL-60 cells was observed at 0.4 μM. Interestingly, the reduction of MMP by DSF was recovered by N-acetyl-L-cysteine, an inhibitor of reactive oxygen species (ROS) production. This suggests that the decrease in MMP by DSF is closely related to the production of ROS in HL-60 cells, which indicates the relationship between the apoptosis of HL-60 cells by DSF and the role of the mitochondria. This study provides clinicians and researchers with valuable information regarding the anti-cancer activity of DSF in terms of the action mechanism.
Keywords
disulfiram; HL-60 cells; mitochondrial membrane potential; cell death; reactive oxygen species;
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1 Xu B, Shi P, Fombon IS, Zhang Y, Huang F, Wang W, Zhou S. Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells. Blood Cells Mol Dis 2011;47:264-269.   DOI
2 Kim SY, Joo HG. Evaluation of adjuvant effects of fucoidan for improving vaccine efficacy. J Vet Sci 2015;16:145-150.   DOI
3 Jang JY, Moon SY, Joo HG. Differential effects of fucoidans with low and high molecular weight on the viability and function of spleen cells. Food Chem Toxicol 2014;68:234-238.   DOI
4 Moon SY, Joo HG. Anti-inflammatory effects of 4,4′-diaminodiphenyl sulfone (dapsone) in lipopolysaccharide-treated spleen cells: selective inhibition of inflammation-related cytokines. Korean J Vet Res 2015;55:199-204.   DOI
5 Navratilova J, Jungova P, Vanhara P, Preisler J, Kanicky V, Smarda J. Copper ions regulate cytotoxicity of disulfiram to myeloid leukemia cells. Int J Mol Med 2009;24:661-670.
6 Park YM, Go YY, Shin SH, Cho JG, Woo JS, Song JJ. Anticancer effects of disulfiram in head and neck squamous cell carcinoma via autophagic cell death. PLoS One 2018;13: e0203069.   DOI
7 Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treat Rev 2009;35:32-46.   DOI
8 Zuo XL, Chen JM, Zhou X, Li XZ, Mei GY. Levels of selenium, zinc, copper, and antioxidant enzyme activity in patients with leukemia. Biol Trace Elem Res 2006;114:41-53.   DOI
9 Cen D, Gonzalez RI, Buckmeier JA, Kahlon RS, Tohidian NB, Meyskens FL Jr. Disulfiram induces apoptosis in human melanoma cells: a redox-related process. Mol Cancer Ther 2002;1:197-204.
10 Eneanya DI, Bianchine JR, Duran DO, Andresen BD. The actions of metabolic fate of disulfiram. Annu Rev Pharmacol Toxicol 1981;21:575-596.   DOI
11 Wang W, McLeod HL, Cassidy J. Disulfiram-mediated inhibition of NF-${\kappa}B$ activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer 2003;104:504-511.   DOI
12 Wickstrom M, Danielsson K, Rickardson L, Gullbo J, Nygren P, Isaksson A, Larsson R, Lovborg H. Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochem Pharmacol 2007;73:25-33.   DOI
13 Shah O'Brien P, Xi Y, Miller JR, Brownell AL, Zeng Q, Yoo GH, Garshott DM, O'Brien MB, Galinato AE, Cai P, Narula N, Callaghan MU, Kaufman RJ, Fribley AM. Disulfiram (Antabuse) activates ROS-dependent ER Stress and apoptosis in oral cavity squamous cell carcinoma. J Clin Med 2019;8:E611.   DOI
14 Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta 2013;1833:3460-3470.   DOI
15 Ron D, Hubbard SR. How IRE1 reacts to ER stress. Cell 2008;132:24-26.   DOI
16 Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 2004;279:45495-45502.   DOI
17 Fang J, Nakamura H, Iyer AK. Tumor-targeted induction of oxystress for cancer therapy. J Drug Target 2007;15:475-486.   DOI
18 Wiley JC, Meabon JS, Frankowski H, Smith EA, Schecterson LC, Bothwell M, Ladiges WC. Phenylbutyric acid rescues endoplasmic reticulum stress-induced suppression of APP proteolysis and prevents apoptosis in neuronal cells. PLoS One 2010;5:e9135.   DOI
19 Halasi M, Wang M, Chavan TS, Gaponenko V, Hay N, Gartel AL. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors. Biochem J 2013;454:201-208.   DOI
20 Mignotte B, Vayssiere JL. Mitochondria and apoptosis. Eur J Biochem 1998;252:1-15.   DOI