Volume 2, Issue 5, September 2014, Page: 88-92
Disulfiram and Copper Gluconate in Cancer Chemotherapy; a Review of the Literature
Georgewill Udeme Owunari, Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, Port Harcourt, Rivers State, Nigeria
Siminialayi Iyeopu Minakiri, Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, Port Harcourt, Rivers State, Nigeria
Received: Sep. 2, 2014;       Accepted: Sep. 16, 2014;       Published: Sep. 30, 2014
DOI: 10.11648/j.crj.20140205.12      View  3046      Downloads  292
Repurposing non- cancer related drugs with possible antitumoral activities is a promising strategy for identifying prospective new anticancer drugs in a cost efficient and time saving way. Repurposing disulfiram has recently become of interest because of its pre-clinically described anticancer effects against various human cancers, which include breast, cervical, colorectal, lung, melanoma, prostate as well as myeloma and leukaemia. Epidemiological studies reveal a trend to reduced cancer risks in cancer patients using disulfiram for chronic alcoholism treatment while already reported literature point to the efficacy of disulfiram on cancer cell lines. Disulfiram has been shown to be effective either as a stand alone or in combination with other drugs against metastatic liver cancer, lung cancer, prostate cancer, glioblastoma and melanoma. Preclinical studies indicate that disulfiram when combined with copper ions acts as a proteasome inhibitor, to induce oxidative stress, reduce NFƙB (Nuclear factor ƙappa Binding) activity and enhance the sensitivity of cancer cells to chemotherapeutic agents. This study analyzed existing literature and found that disulfiram in combination with copper gluconate is a promising therapeutic agent for use in cancer chemotherapy.
Cancer, Disulfiram, Copper gluconate
To cite this article
Georgewill Udeme Owunari, Siminialayi Iyeopu Minakiri, Disulfiram and Copper Gluconate in Cancer Chemotherapy; a Review of the Literature, Cancer Research Journal. Vol. 2, No. 5, 2014, pp. 88-92. doi: 10.11648/j.crj.20140205.12
Ferlay J, Shin HR, Bray F, Forman D, Mathers CD, Parkin D. GLOBO-CAN 2008, Cancer Incidence and Mortality Worldwide: IARC Cancer-Base No.10 [Internet]. Lyon, France: International Agency for Research on Cancer. 2010; Available from: http://globocan.iarc.fr.
World Health Organization. World Cancer Report 2008. Lyon: Inter- national Agency for Research on Cancer;2008
Chukwuma, M.(2006). Crude oil pollution raises cancer risk among Nigerians. African Cancer Centre
Nwankwoala R,Georgewill O.A(2006) “ Analysis of the occurrence of cancerand other tumours in rivers and bayelsa states, Nigeria from December1997 to December 2000”. African Journal of applied zoology and Environmentalbiology,2006. Vol 8,48-53
US Patent 1782111 - Method of Manufacturing Tetra-alkylated Thiuramdisulphides
Chen S.H, Liu S.H, Liang Y.C, Lin J.K, Lin-Shiau S.Y.(2001). Oxidative stress and c-Junamino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu21 complex. Eur J Pharmacol. 414:177–188
Cen D, Gonzalez R.I, Buckmeier J.A, Kahlon R.S, Tohidian N.B, Meyskens F.L Jr(2002). Disulfiram induces apoptosis in human melanoma cells: a redox-related process.Mol Cancer Ther. 1:197–204.
Daniel KG, Chen D, Yan B, Dou QP (2008). Copper-binding compounds as proteasome Discov Today.13:716–722.
Gupte A,Mumper J(2009) Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer treatment reviews. Vol 35;32-46
Chen D, Cui Q.C, Yang H, Dou Q.P(2006). 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 66: 10425-33.
Wickstrom M, Danielsson K, Rickardson L, Gullbo J, Nygren P, Isaksson A, et al.(2007). Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochem Pharmacol 2007; 73: 25-33.
Maupin-Furlow J.A, Humbard M.A, Kirkland P.A, Li W, Reuter C.J, Wright A.J, et al(2006). Proteasomes from structure to function: perspectives from archaea. Curr Top Dev Biol 75: 125-69
Hershko, A(2005). The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 12: 1191-7
Sutovsky P, Van Leyen K, McCauley T, Day B.N, Sutovsky M.(2004) Degradation of paternal mitochondria after fertilization: implications for heteroplasmy, assisted reproductive technologies and mtDNA inheritance. Reprod Biomed Online 8: 24-33
Ferdous A, Gonzalez F, Sun L, Kodadek. T, Johnston S.A(2001). The 19S regulatory particle of the proteasome is required for efficient transcription elongation by RNA polymerase II. Mol Cell 7: 981-91.
Gonzalez F, Delahodde A, Kodadek T, Johnston S.A.(2002). Recruitment of a 19S proteasome subcomplex to an activated promoter. Science; 296: 548-50
Lovborg H, Oberg F., Rickardson L, Gullbo J, Nygren P, Larsson R.(2006). Inhibition of proteasome activity, nuclear factor-KB translocation and cell survival by the antialcoholism drug disulfiram. Int. J Cancer.118:1577–1580.
Matsuno T, Kariya R, Yano S, (2012). Diethyldithiocarbamate induces apoptosis in HHV-8-infected primary effusion lymphoma cells via inhibition of the NF-kappaB pathway. Int J Oncol, 40, 1071-8.
Cvek B, Dvorak Z (2007). Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes with metals. Curr Pharm Des, 13, 3155-67
Colin Rae (2013). The Role of Copper in Disulfiram-Induced Toxicity And Radiosensitization of Cancer Cells. Journal of Nuclear Medicine, doi:10.2967/jnumed.112.113324
Yoshida Y, Wang IC, Yoder HM, Davidson NO, Costa RH.(2007)” The forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer”. Gastroenterology.132:1420–1431. doi: 10.1053/j.gastro.2007.01.036
Vasiliou V, Pappa A, Petersen DR(2000) Role of aldehyde dehydrogenases in endogenous and xenobiotic metabolism. Chem Biol Interact 129:1–19.
Sophos NA, Vasiliou V(2003) Aldehyde dehydrogenase gene superfamily: the 2002 update. Chem Biol Interact 143–144:5–22.
Vasiliou V, Nebert DW(2005) Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics 2:138–143
Marchitti SA, Brocker C, Stagos D, Vasiliou V(2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 4:697–720.
Niederreither K, Dollé P(2008) Retinoic acid in development: towards an integrated view. Nat Rev Genet 9:541–553.
Kim KJ, Pearl PL, Jensen K, Snead OC, Malaspina P, Jakobs C, Gibson KM(2011a) Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance. Antioxid Redox Signal 15:691–718.
Moore SA, Baker HM, Blythe TJ, Kitson KE, Kitson TM, Baker EN(1998) Sheep liver cytosolic aldehyde dehydrogenase: the structure reveals the basis for the retinal specificity of class 1 aldehyde dehydrogenases. Structure 6:1541–1551.
Deitrich RA, Erwin VG(1971) Mechanism of the inhibition of aldehyde dehydrogenase in vivo by disulfiram and diethyldithiocarbamate. Mol Pharmacol 7:301–307.
Vallari RC, Pietruszko R(1982) Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram. Science 216:637–639.
Kitson TM(1983) Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram. Biochem J 213:551–554.
Lipsky JJ, Shen ML, Naylor S(2001) In vivo inhibition of aldehyde dehydrogenase by disulfiram. Chem Biol Interact 130–132:93–102.
Hart BW, Faiman MD(1995) Inhibition of rat liver low Km aldehyde dehydrogenase by thiocarbamate herbicides. Occupational implications. Biochem Pharmacol 49:157–163.
Mays DC, Nelson AN, Lam-Holt J, Fauq AH, Lipsky JJ(1996) S-methyl-N,N-diethylthiocarbamate sulfoxide and S-methyl-N,N-diethylthiocarbamate sulfone, two candidates for the active metabolite of disulfiram. Alcohol Clin Exp Res 20:595–600.
Mays DC, Ortiz-Bermudez P, Lam JP, Tong IH, Fauq AH, Lipsky JJ (1998) Inhibition of recombinant human mitochondrial aldehyde dehydrogenase by two intermediate metabolites of disulfiram. Biochem Pharmacol 55:1099–1103.
Staub RE, Quistad GB, Casida JE(1999) S-methyl N-butylthiocarbamate sulfoxide: selective carbamoylating agent for mouse mitochondrial aldehyde dehydrogenase. Biochem Pharmacol 58:1467–1473
Shen ML, Johnson KL, Mays DC, Lipsky JJ, Naylor S.(2001) Determination of in vivo adducts of disulfiram with mitochondrial aldehyde dehydrogenase. Biochem Pharmacol 61:537–545.
NRC (1980) Recommended dietary allowances. Food and Nutrition Board,National Research Council and National Academy of Sciences, Washington, D.C.
Araya M, Olivares M, Pizarro F, Méndez Ma, González M, Uauy R(2005). Supplementing copper at the upper level of the adult dietary recommended intake induces detectable but transient changes in healthy adults. J Nutr. 135:2367-2371.
Bügel S, Harper A, Rock E, O'Conner JM, Bonham MP, Strain JJ.(2005). Effect of copper supplementation on indices of copper status and certain CVD risk markers in young healthy women. Br J Nutr. 94:231-236.
Habib FK, Dembinski TC, Stitch SR.(1980). The zinc and copper content of blood leucocytes and plasma from patients with benign and malignant prostates. Clin Chim Acta. 104:329–335. [PubMed
Rizk SL, Sky-Peck HH (1984). Comparison between concentrations of trace elements in normal and neoplastic human breast tissue. Cancer Res. 44:5390–5394. [PubMed]
Turecky L, Kalina P, Uhlikova E,(1984). Serum ceruloplasmin and copper levels in patients with primary brain tumors. Klin Wochenschr. 62:187–189. [PubMed
Diez M, Arroyo M, Cerdan FJ,(1989). Serum and tissue trace metal levels in lung cancer. Oncology. 46:230–234. [PubMed]
Huang YL, Sheu JY, Lin TH (1999). Association between oxidative stress and changes of trace elements in patients with breast cancer. Clin Biochem. 32:131–136. [PubMed]
Kuo HW, Chen SF, Wu CC.(2002). Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol Trace Elem Res. 89:1–11. [PubMed
Nayak SB, Bhat VR, Upadhyay D,(2003). Copper and ceruloplasmin status in serum of prostate and colon cancer patients. Indian J Physiol Pharmacol. 47:108–110. [PubMed]
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