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Synergistic anticancer activity of disulfiram/copper against mouse lymphoma cells

마우스 림프종세포에 대한 disulfiram/copper의 항암증진효과

  • Jung, Haebeen (Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Jeju National University) ;
  • Joo, Hong-Gu (Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, Jeju National University)
  • 정해빈 (제주대학교 수의과대학 수의약리학실) ;
  • 주홍구 (제주대학교 수의과대학 수의약리학실)
  • Received : 2021.10.05
  • Accepted : 2021.11.29
  • Published : 2022.03.31

Abstract

Disulfiram (DSF) is a marketed drug to treat patients with alcohol dependence by inhibiting aldehyde dehydrogenase. Over the last few decades, DSF has been shown to have anticancer effects through different mechanisms. Moreover, this effect can be elevated when used with copper (Cu). Subsequent studies have been conducted on various cancers, but few on lymphoma. This study investigated the anticancer effects of DSF on lymphoma and how this effect changed when treated with Cu. DSF synergistically decreased the metabolic activity of EL4 lymphoma cells when combined with Cu. At 1 µM of DSF alone, the metabolic activity of EL4 cells decreased by 49% compared to the control, whereas it decreased by 87% with a DSF + CuCl2 treatment. Rhodamine 123 and 2',7'-dichlorofluorescein diacetate staining showed that DSF induced the reduction of the mitochondrial membrane potential and promoted the production of reactive oxygen species. In particular, the combined treatment of DSF + Cu induced cell death based on multiple assays, including annexin V-fluorescein isothiocyanate/propidium iodide staining. Overall, DSF has anticancer effects on lymphoma cells and exhibits synergistic effects when combined with Cu. This study provides some valuable information to broaden the use of DSF in clinics and basic research.

Keywords

References

  1. Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand Suppl 1992;369:15-26. https://doi.org/10.1111/j.1600-0447.1992.tb03310.x
  2. Suh JJ, Pettinati HM, Kampman KM, O'Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol 2006;26:290-302. https://doi.org/10.1097/01.jcp.0000222512.25649.08
  3. Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, Ozdian T, Bartkova J, Turi Z, Moudry P, Kraus M, Michalova M, Vaclavkova J, Dzubak P, Vrobel I, Pouckova P, Sedlacek J, Miklovicova A, Kutt A, Li J, Mattova J, Driessen C, Dou QP, Olsen J, Hajduch M, Cvek B, Deshaies RJ, Bartek J. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 2017;552:194-199. https://doi.org/10.1038/nature25016
  4. Yang Z, Guo F, Albers AE, Sehouli J, Kaufmann AM. Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed Pharmacother 2019;113:108727. https://doi.org/10.1016/j.biopha.2019.108727
  5. Chen D, Cui QC, Yang H, Dou QP. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res 2006;66: 10425-10433. https://doi.org/10.1158/0008-5472.CAN-06-2126
  6. Guo X, Xu B, Pandey S, Goessl E, Brown J, Armesilla AL, Darling JL, Wang W. Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines. Cancer Lett 2010;290:104-113. https://doi.org/10.1016/j.canlet.2009.09.002
  7. Butcher K, Kannappan V, Kilari RS, Morris MR, McConville C, Armesilla AL, Wang W. Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line. BMC Cancer 2018; 18:753. https://doi.org/10.1186/s12885-018-4617-x
  8. Lun X, Wells JC, Grinshtein N, King JC, Hao X, Dang NH, Wang X, Aman A, Uehling D, Datti A, Wrana JL, Easaw JC, Luchman A, Weiss S, Cairncross JG, Kaplan DR, Robbins SM, Senger DL. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clin Cancer Res 2016;22:3860-3875. https://doi.org/10.1158/1078-0432.CCR-15-1798
  9. Xu Y, Zhou Q, Feng X, Dai Y, Jiang Y, Jiang W, Liu X, Xing X, Wang Y, Ni Y, Zheng C. Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways. Biomed Pharmacother 2020;126:110048. https://doi.org/10.1016/j.biopha.2020.110048
  10. Iljin K, Ketola K, Vainio P, Halonen P, Kohonen P, Fey V, Grafstrom RC, Perala M, Kallioniemi O. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res 2009;15:6070-6078. https://doi.org/10.1158/1078-0432.ccr-09-1035
  11. Crowley LC, Marfell BJ, Waterhouse NJ. Analyzing cell death by nuclear staining with Hoechst 33342. Cold Spring Harb Protoc 2016;2016.
  12. Huang M, Camara AK, Stowe DF, Qi F, Beard DA. Mitochondrial inner membrane electrophysiology assessed by rhodamine-123 transport and fluorescence. Ann Biomed Eng 2007;35:1276-1285. https://doi.org/10.1007/s10439-007-9265-2
  13. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao PJ, Achanta G, Arlinghaus RB, Liu J, Huang P. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 2006;10:241-252. https://doi.org/10.1016/j.ccr.2006.08.009
  14. Zheng J, Lou JR, Zhang XX, Benbrook DM, Hanigan MH, Lind SE, Ding WQ. N-Acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death. Cancer Lett 2010;298:186-194. https://doi.org/10.1016/j.canlet.2010.07.003
  15. Agarwal RP, Phillips M, McPherson RA, Hensley P. Serum albumin and the metabolism of disulfiram. Biochem Pharmacol 1986;35:3341-3347. https://doi.org/10.1016/0006-2952(86)90433-8
  16. Wang Z, Tan J, McConville C, Kannappan V, Tawari PE, Brown J, Ding J, Armesilla AL, Irache JM, Mei QB, Tan Y, Liu Y, Jiang W, Bian XW, Wang W. Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stemlike cells. Nanomedicine 2017;13:641-657. https://doi.org/10.1016/j.nano.2016.08.001
  17. Lee MS, Dees EC, Wang AZ. Nanoparticle-delivered chemotherapy: old drugs in new packages. Oncology (Williston Park) 2017;31:198-208.