Elevated copper and oxidative stress in cancer cells as a target for cancer treatment

  • Anshul Gupte
    Affiliations
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, United States

    Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, NC 27599-7360, United States
    Search for articles by this author
  • Russell J. Mumper
    Correspondence
    Corresponding author. Address: Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, CB # 7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, United States. Tel.: +1 919 966 1271; fax: +1 919 966 0197.
    Affiliations
    Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599-7360, United States

    Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, NC 27599-7360, United States

    UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599-7295, United States
    Search for articles by this author
Published:September 09, 2008DOI:https://doi.org/10.1016/j.ctrv.2008.07.004

      Summary

      As we gain a better understanding of the factors affecting cancer etiology, we can design improved treatment strategies. Over the past three to four decades, there have been numerous successful efforts in recognizing important cellular proteins essential in cancer growth and therefore these proteins have been targeted for cancer treatment. However, studies have shown that targeting one or two proteins in the complex cancer cascade may not be sufficient in controlling and/or inhibiting cancer growth. Therefore, there is a need to examine features which are potentially involved in multiple facets of cancer development. In this review we discuss the targeting of the elevated copper (both in serum and tumor) and oxidative stress levels in cancer with the aid of a copper chelator d-penicillamine (d-pen) for potential cancer treatment. Numerous studies in the literature have reported that both the serum and tumor copper levels are elevated in a variety of malignancies, including both solid tumor and blood cancer. Further, the elevated copper levels have been shown to be directly correlated to cancer progression. Enhanced levels of intrinsic oxidative stress has been shown in variety of tumors, possibly due to the combination of factors such as elevated active metabolism, mitochondrial mutation, cytokines, and inflammation. The cancer cells under sustained ROS stress tend to heavily utilize adaptation mechanisms and may exhaust cellular ROS-buffering capacity. Therefore, the elevated copper levels and increased oxidative stress in cancer cells provide for a prospect of selective cancer treatment.

      Abbreviations:

      ROS (reactive oxygen species), d-pen (d-penicillamine), Cu (copper), H2O2 (hydrogen peroxide), GSH (Glutathione), GSSG (Glutathione disulfide), SOD (superoxide dismutase)

      Keywords

      To read this article in full you will need to make a payment

      References

        • Harris Z.H.
        • Gitlin J.D.
        Genetic and molecular basis of copper toxicity.
        Am J Clin Nutr. 1996; 63: 836S-841S
        • Tapiero H.
        • Townsend D.M.
        • Tew K.D.
        Trace elements in human physiology and pathology.
        Copper Biomed Pharmcother. 2003; 57: 386-398
        • Gaetke L.M.
        • Chow C.K.
        Copper toxicity, oxidative stress, and antioxidant nutrients.
        Toxicology. 2003; 189: 147-163
        • Lonnerdal B.
        Bioavailability of copper.
        Am J Clin Nutr. 1996; 63: 821S-829S
        • Valko M.
        • Morris H.
        • Cronin M.T.D.
        Metals, toxicity and oxidative stress.
        Curr Med Chem. 2005; 12: 1161-1208
        • Wang T.
        • Guo Z.
        Copper in medicine: homeostasis, chelation therapy and anti-tumor drug design.
        Curr Med Chem. 2006; 13: 525-537
        • Turnlund J.R.
        Human whole body copper metabolism.
        Am J Clin Nutr. 1998; 67: 960S-964S
        • Hellman N.E.
        • Gitlin J.D.
        Ceruloplasmin metabolism and function.
        Ann Rev Nutr. 2002; 22: 439-458
        • Linder M.C.
        • Wooten L.
        • Cerveza P.
        • Cotton S.
        • Shulze R.
        • Lomeli N.
        Copper transport.
        Am J Clin Nutr. 1998; 67: 965S-971S
        • Brewer G.
        Anticopper therapy against cancer and diseases of inflammation and fibrosis.
        Drug Dis Today. 2005; 10: 1103-1109
        • Goodman V.L.
        • Brewer G.J.
        • Merajver S.D.
        Copper deficiency as an anti-cancer strategy.
        Endocr Relat Cancer. 2004; 11: 255-263
        • Apelgot S.
        • Coppey J.
        • Fromentin A.
        • Guille E.
        • Poupon M.-F.
        • Roussel A.
        Altered distribution of copper (64Cu) in tumor-bearing mice and rats.
        Anticancer Res. 1986; 6: 159-164
        • Semczuk B.
        • Pomykalski M.
        Serum copper level in patients with laryngeal carcinoma.
        Otolaryngial Pol. 1973; 27: 17-23
        • Tani P.
        • Kokkola K.
        Serum iron, copper and iron binding capacity in bronchogenic pulmonary carcinoma.
        Scand J Res Dis. 1972; 80: 121-128
        • Kuo K.W.
        • Chen S.F.
        • Wu C.C.
        • Chen D.R.
        • Lee J.H.
        Serum and tissue trace elements in patients with breast cancer in Taiwan.
        Biol Trace Elem Res. 2002; 89: 1-11
        • Hrgovic M.
        • Tessmer C.F.
        • Forrest B.
        Cancer. 1973; 31: 1337-1345
        • Linder M.C.
        • Moor J.R.
        • Wright K.
        Tumori. 1981; 65: 331-338
        • Scanni A.
        • Licciardello L.
        • Trovato M.
        • Tomirotii M.
        • Biraghi M.
        Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung.
        Tumori. 1977; 63: 175-180
        • Zuo X.L.
        • Chen J.M.
        • Zhou X.
        • Li X.Z.
        • Mei G.Y.
        Levels of selenium, zinc, copper and antioxidant enzyme activity in patients with leukemia.
        Biol Trace Elem Res. 2006; 114: 41-54
        • Chan A.
        • Wong F.
        • Arumanayagam M.
        Serum ultrafiltrable copper, total copper and ceruloplasmin concentrations in gynecological carcinoma.
        Ann Clin Biochem. 1993; 30: 545-549
        • Diez M.
        • Arroyo M.
        • Cerdan F.J.
        • Munoz M.
        • Martin M.A.
        • Balibrea J.L.
        Serum and tissue trace metal levels in lung cancer.
        Oncology. 1989; 46: 230-234
        • Habib F.K.
        • Dembinski T.C.
        • Stitch S.R.
        The zinc and copper content of blood leukocytes and plasma from patients with benign and malignant prostates.
        Clin Chim Acta. 1980; 104: 329-335
        • Margalioth E.J.
        • Schenker J.G.
        • Chevion M.
        Copper and zinc levels in normal and malignant tissues.
        Cancer. 1983; 52: 868-872
        • Rajput V.S.
        • Gupta S.N.
        • Sur B.K.
        • Pandey R.P.
        • Singh S.
        An evaluation of serum copper levels in diagnosis of various malignancies.
        Indian J Surg. 1979; 5: 515-519
        • Carpentieri U.
        • Myers J.
        • Thorpe L.
        • Daeschner C.W.
        • Haggard M.E.
        Copper, zinc and iron in normal and leukemic lymphocytes from children.
        Cancer Res. 1986; 46: 981-984
        • Jayadeep A.
        • Pillai K.R.
        • Kannan S.
        • Nalinaumari K.R.
        • Mathew B.
        • Nair M.K.
        • et al.
        Serum levels of copper, zinc, iron and ceruloplasmin in oral leukoplakia and squamous cell carcinoma.
        J Exp Clin Cancer Res. 1997; 16: 295-300
        • Lightman A.
        • Brandes J.M.
        • Binur N.
        • Drugan A.
        • Zinder O.
        Use of serum copper/zinc ratio in the differential diagnosis of ovarian malignancy.
        Clin Chem. 1986; 32: 101-103
        • Folkman J.
        • Klagsbrun M.
        Angiogenic factors.
        Science (New York, NY). 1987; 235: 442-447
        • Lowndes S.A.
        • Harris A.L.
        Copper chelation as an antiangiogenic therapy.
        Oncol Res. 2004; 14: 529-539
        • Lowndes S.A.
        • Harris A.L.
        The role of copper in tumor angiogenesis.
        J Mamm Gland Niol Neoplasia. 2005; 10: 299-310
        • Brem S.
        Angiogenesis and cancer control: from concept to therapeutic trial.
        Cancer Control. 1999; 6: 436-458
        • Raju K.S.
        • Alessandri G.
        • Ziche M.
        • Gullino P.M.
        Ceruloplasmin, copper ions and angiogenesis.
        J Natl Cancer Ins. 1982; 69: 1183-1188
        • Hu G.
        Copper stimulates proliferation of human endothelial cells under culture.
        J Cellular Biochem. 1998; 69: 326-335
        • Gullino P.M.
        Considerations on the mechanisms of the antiangiogenic response.
        Anticancer Res. 1986; 6: 153-158
        • Kochi N.
        • Morimura T.
        • Itagaki T.
        Immunohistochemical study of fibronectin in human glioma and meningioma.
        Acta Neuropathol (Berl). 1983; 59: 119-126
        • Parke A.
        • Bhattacherjee P.
        • Palmer R.M.J.
        • Lazarus N.R.
        Characterization and quantification of copper sulfate-induced vascularization of the rabbit cornea.
        Am J Pathol. 1988; 130: 173-178
        • Brem S.S.
        • Zagzag D.
        • Tsanaclis A.M.
        • Gately S.
        • Elkouby M.P.
        • Brien S.E.
        Inhibition of angiogenesis and tumor growth in the brain Suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor..
        Am J Pathol. 1990; 137: 1121-1142
        • Geraki K.
        • Farquharson M.J.
        • Bradley D.A.
        Concentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study.
        Phys Med Niol. 2002; 47: 2327-2339
        • Finney L.
        • Mandava S.
        • Ursos L.
        • Zhang W.
        • Rodi D.
        • Vogt S.
        • et al.
        X-ray fluorescence microscopy reveals large scale relocalization and extracellular translocation of cellular copper during angiogenesis.
        PNAS. 2007; 104: 2247-2252
        • Camphausen K.
        • Sproull M.
        • Tantama S.
        • Venditto V.
        • Sankineni S.
        • Scott T.
        • et al.
        Evaluation of chelating agents as anti-angiogenic therapy through copper chelation.
        Bioorg Med Chem. 2004; 12: 5133-5140
        • Pan Q.
        • Kleer C.G.
        • van Golen K.L.
        • Irani J.
        • Bottema K.M.
        • Bias C.
        • et al.
        Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis.
        Cancer Res. 2002; 62: 4854-4859
        • Ding W.-Q.
        • Liu B.
        • Vaught J.L.
        • Yamauchi H.
        • Lind S.E.
        Anticancer activity of the antibiotic clioquinol.
        Cancer Res. 2005; 65: 3389-3395
        • Hayashi M.
        • Nishiya H.
        • Chiba T.
        • Endoh D.
        • Kon Y.
        • Ohui T.
        Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cell in-vivo and in-vitro.
        Lab Animal Sci. 2007; 69: 137-142
        • Pan Q.
        • Kleer C.G.
        • van Golen K.L.
        • Irani J.
        • Bottema K.M.
        • Bias C.
        • et al.
        Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis.
        Cancer Res. 2002; 62: 4854-4859
        • Khan M.K.
        • Miller M.W.
        • Taylor J.
        • Gill N.K.
        • Dick R.D.
        • Van Golen K.
        • et al.
        Radiotherapy and antiangiogenic TM in lung cancer.
        Neoplasia (New York, NY). 2002; 4: 164-170
        • Moriguchi M.
        • Nakajima T.
        • Kimura H.
        • Watanabe T.
        • Takashima H.
        • Mitsumoto Y.
        • et al.
        The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin-8 production.
        Int J Cancer. 2002; 102: 445-452
        • Yoshida D.
        • Ikeda Y.
        • Nakazawa S.
        Suppression of tumor growth in experimental 9L gliosarcoma model by copper depletion.
        Neurol Medico-Chirurg. 1995; 35: 133-135
        • Brem S.S.
        • Zagzag D.
        • Tsanaclis A.M.
        • Gately S.
        • Elkouby M.P.
        • Brien S.E.
        Inhibition of angiogenesis and tumor growth in the brain suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor.
        Am J Path. 1990; 137: 1121-1142
        • Pan Q.
        • van Golen K.L.
        • Irani J.
        • Bottema K.M.
        • Bias C.
        • De Carvalho M.
        • et al.
        Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis.
        Cancer Res. 2002; 62: 4854-4859
        • Brem S.
        • Grossman S.A.
        • Carson K.A.
        • New P.
        • Phuphanisch S.
        • Alavi J.B.
        • et al.
        Phase II trial of copper depletion and penicillamine as antiangiogenesis therapy of gioblastoma.
        Neuro-Oncology. 2005; 7: 246-253
        • Brewer G.J.
        • Dick R.D.
        • Grover D.K.
        • LeClaire V.
        • Tseng M.
        • Pienta K.
        • et al.
        Treatment of metastatic cancer with tetrathiomolybedate, an anticopper, antiangiogenic agent: Phase I study.
        Clin Cancer Res. 2000; 6: 1-10
        • Redman B.G.
        • Esper P.
        • Pan Q.
        • Dunn R.L.
        • Hussain H.K.
        • et al.
        Phase II trial of tetrathiomolybdate in patients with advanced kidney cancer.
        Clin Cancer Res. 2003; 9: 1666-1672
        • Poli G.
        • Biasi F.
        • Chiarpotto E.
        Oxidative stress and cell signaling.
        Curr Med Chem. 2004; 11: 1163-1182
        • Chandra J.
        • Samali A.
        • Orrenius S.
        Triggering and modulation of apoptosis by oxidative stress.
        Free Rad Med Biol. 2000; 29: 323-333
        • Floyd R.A.
        Role of oxygen free radicals in carcinogenesis and brain ischemia.
        FASEB J. 1990; 4: 2587-2597
        • Dandona P.
        • Cook S.
        • Synder B.
        • Makowski J.
        Oxidative damage to DNA in diabeted mellitus.
        Lancet. 1996; 347: 444-445
        • Valko M.
        • Leibfritz D.
        • Moncol J.
        • Cronin M.T.D.
        • Mazur M.
        • et al.
        Free radicals and antioxidants in normal physiological functions and human disease.
        Int J Biochem Cell Biol. 2007; 39: 44-84
        • Jenner P.
        Oxidative damage in neurodegenerative diseases.
        Lancet. 1994; 344: 796-798
        • Ames B.N.
        • Shigenaga M.K.
        Oxidants are a major contributor to aging.
        Ann NY Acad Sci. 1992; 663: 85-96
        • Pervaiz S.
        • Clement M.V.
        Tumor intracellular redox status and drug resistance-serendipity or a causal relationship?.
        Curr Pharm Des. 2004; 10: 1969-1977
        • Powis G.
        • Baker A.
        Redox signaling and the control of cell growth and death.
        Adv Pharmacol. 1997; 38: 329-359
        • Farber J.L.
        • Kyle M.E.
        • Coleman J.B.
        Mechanisms of cell injury by activated oxygen species.
        Lab Invest. 1990; 62: 670-679
        • Federico A.
        • Tuccillo C.
        • Ciardiello F.
        • Loguercio C.
        Chronic inflammation and oxidative stress in human carcinogenesis.
        Int J Cancer. 2007; 121: 2381-2386
        • Nair U.
        • Nair J.
        Lipid peroxidation-induced DNA damage in cancer-prone inflammatory diseases: a review of published adduct types and levels in humans.
        Free Rad Biol Med. 2007; 43: 1109-1120
        • Behrend L.
        • Henderson G.
        • Zwacka R.M.
        Reactive oxygen species in oncogenic transformation.
        Biochem Soc Trans. 2003; 31: 1441-1444
        • Gate L.
        • Paul J.
        • Ba G.N.
        • Tew K.D.
        • Tapiero H.
        Oxidative stress induced in pathologies: the role of antioxidants.
        Biomed Pharmcother. 1999; 53: 169-180
        • Farber J.L.
        Mechanism of cell injury by activated oxygen species.
        Env Health Perspect. 1994; 102: 17-24
        • Imlay J.A.
        DNA damage and oxygen radical toxicity.
        Science (New York, NY). 1988; 240: 1302-1309
        • Hoffman M.E.
        • Meneghini R.
        Correlation between cytotoxic effect of hydrogen peroxide and the yield of DNA strand breaks in cells of different species.
        Biocim Biophys Acta. 1984; 781: 234-238
        • Fruehauf J.P.
        • Meyskens F.L.
        Reactive oxygen species: A breath of life or death?.
        Clin Cancer Res. 2007; 13: 789-794
        • Sohal R.S.
        Oxidative stress, caloric restriction, and aging.
        Science (New York, NY). 1996; 273: 59-63
        • Valko M.
        • Izakovic M.
        • Mazur M.
        • Rhodes C.J.
        • Telser J.
        Role of oxygen radicals in DNA damage and cancer incidence.
        Mol Cell Biochem. 2004; 266: 37-56
        • Monteiro H.P.
        • Stern A.
        Redox modulation of tyrosine phosphorylation-dependent signal transduction pathways.
        Free Rad Biol Med. 1996; 21: 323-333
        • Oberley T.D.
        Oxidative damage and cancer.
        Am J Path. 2002; 160: 403-408
        • Li J.J.
        • Fan M.
        • Colburn N.H.
        Inhibition of AP-1 and NF-kappa B by manganese-containing superoxide dismutase in human breast cancer cells.
        FASEB J. 1998; 12: 1713-1723
        • Orrenius S.
        Reactive oxygen species in mitochondria-mediated cell death.
        Drug Metab Rev. 2007; 39: 443-455
        • Fang J.
        • Iyer A.K.
        Tumor-targeted induction of oxystress for cancer therapy.
        J Drug Targ. 2007; 15: 475-486
        • Nulton-Persson A.C.
        Modulation of mitochondrial function by hydrogen peroxide.
        J Biol Chem. 2001; 276: 23357-23361
        • Castro L.
        Reactive oxygen species in human health and disease.
        Nutrition. 2001; 17: 161-165
        • Valko M.
        • Rhodes C.J.
        • Moncol J.
        • Izakovic M.
        • Mazur M.
        Free radicals, metals and antioxidants in oxidative stress-induced cancer.
        Chemico-Biol Interact. 2006; 160: 1-40
        • Inoue M.
        • Nishikawa M.
        • Park A.M.
        • Kira Y.
        • Imada I.
        • Utsumi K.
        Mitochondrial generation of reactive oxygen species and its role in aerobic life.
        Curr Med Chem. 2003; 10: 2495-2505
        • Cadenas E.
        Biochemistry of oxygen toxicity.
        Annu Rev Biochem. 1989; 58: 205-209
        • Parke D.V.
        Chemical toxicity and reactive oxygen species.
        Int J Occup Med Environ Health. 1996; 9: 331-340
        • Halliwell B.
        • Clement M.V.
        • Long L.H.
        Hydrogen peroxide in the human body.
        FEBS Lett. 2000; 486: 10-13
        • Aust S.A.
        • Morehouse L.A.
        • Thomas C.E.
        Role of metals in oxygen radical reactions.
        J Free Rad Biol Med. 1985; 1: 3-25
        • Buettner G.R.
        The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate.
        Arch Biochem Biophys. 1993; 300: 535-543
        • Sasaki K.
        • Bannai S.
        • Makino N.
        Kinetics of hydrogen peroxide elimination by human umbilical vein endothelial cells in culture.
        Biochem Biophys Acta. 1998; 1380: 275-288
        • Antunes F.
        • Cadneas E.
        Estimation of H2O2 gradient across biomembranes.
        FEBS Lett. 2000; 475: 121-126
        • Halliwell B.
        Oxygen toxicity, oxygen radicals, transition metals and diseases.
        Biochem J. 1984; 219: 1-14
        • Burdon R.H.
        Superoxide and hydrogen peroxide in relation to mammalian cell proliferation.
        Free Rad Med Biol. 1995; 18: 775-794
        • Burdon R.H.
        • Rice-Evans C.
        Oxidative stress and tumour cell proliferation.
        Free Rad Res Commun. 1990; 11: 65-76
        • Burdon R.H.
        • Rice-Evans C.
        Cell proliferation and oxidative stress.
        Free Rad Res Commun. 1989; 7: 149-159
        • Gupte A.
        • Mumper R.J.
        Copper chelation by d-penicillamine generates reactive oxygen species that are cytotoxic to human leukemia and breast cancer cells.
        Free Rad Biol Med. 2007; 43: 1271-1278
        • Devi G.S.
        • Prasad M.H.
        • Saraswathi I.
        • Raghu D.
        • Rao D.N.
        • Reddy P.P.
        Free radicals antioxidant enzymes and lipid peroxidation in different types of leukemia.
        Clin Chim Acta. 2000; 293: 53-62
        • Pelicano H.
        • Carney D.
        • Huang P.
        ROS stress in cancer cells and therapeutic implications.
        Drug Resist Updates. 2004; 7: 97-110
        • Pervaiz S.
        Pro-oxidant milieu blunts scissors: insight into tumor progression, drug resistance, and novel druggable targets.
        Curr Pharm Chem. 2006; 12: 4469-4477
        • Chaiswing L.
        • Bourdeau-Heller J.M.
        • Zong W.
        • Oberley T.D.
        Characterization of redox state of two human prostate carcinoma cell lines with different degrees of aggressiveness.
        Free Rad Biol Med. 2007; 43: 202-215
        • Kondo S.
        • Toyokuni S.
        • Iwasa Y.
        • Tanaka T.
        • Onodera H.
        • Hiai H.
        • et al.
        Persistent oxidative stress in human colorectal carcinoma, but not adenoma.
        Free Rad Biol Med. 1999; 27: 401-410
        • Senthil K.
        • Aranganathan S.
        • Nalini N.
        Evidence of oxidative stress in the circulation of ovarian cancer patients.
        Clin Chim Acta. 2004; 339: 27-32
        • Aydin A.
        • Aesova-Sarafinovska Z.
        • Sayal A.
        • Eken A.
        • Erdem O.
        • Erten K.
        • et al.
        Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostatic hyperplasia.
        Clin Biochem. 2006; 39: 176-179
        • Ho H.O.
        • Chan-Yeung M.
        • Ho S.P.
        • Mak J.C.
        • Ip M.S.
        • Ooi M.S.
        • et al.
        Disturbance of systemic antioxidant profile in nonsmall cell lung carcinoma.
        Eur Resp J. 2007; 29: 273-278
        • Beevi S.S.
        • Rasheed M.H.
        • Geetha A.
        Evidence of oxidative and nitrosative stress in patients with cervical squamous cell carcinoma.
        Clin Chim Acta. 2007; 375: 119-123
        • Batchioglu K.
        • Mehmet N.
        • Ozturk I.C.
        • Yilmaz M.
        • Aydogdu N.
        • Erguvan R.
        • et al.
        Lipid peroxidation and antioxidant status in stomach cancer.
        Cancer Invest. 2006; 24: 18-21
        • Guven M.
        • Ozturk B.
        • Sayal A.
        • Ozet A.
        Lipid peroxidation and antioxidant system in blood of patients with Hodgkin’s disease.
        Clin Biochem. 2000; 33: 209-212
        • Navarro J.
        • Obrador E.
        • Carretero J.
        • Petschen I.
        • Avino J.
        • Perez P.
        • et al.
        Changes in glutathione status and the antioxidant system in blood and in cancer cells associate with tumor growth in-vivo.
        Free Rad Med Biol. 1999; 26: 410-418
        • Yeh C.-C.
        • Hou M.-F.
        • Tsai S.-M.
        • Lin S.-K.
        • Hsiao J.-K.
        • Huang J.-C.
        • et al.
        Superoxide anion radical, lipid peroxides and antioxidant status in the blood of patients with breast cancer.
        Clin Chim Acta. 2005; 361: 101-111
        • Khanzode S.S.
        • Muddeshwar M.G.
        • Khanzode S.D.
        • Dakhale G.N.
        Antioxidant enzymes and lipid peroxidation in different stages of breast cancer.
        Free Rad Res. 2004; 38: 81-85
        • Kumaraguruparan R.
        • Subapriya R.
        • Kablimoorthy J.
        • Nagini S.
        Antioxidant profile in the circulation of patients with fibroadenoma and adenocarcinoma of the breast.
        Clin Biochem. 2002; 35: 275-279
        • Sener D.E.
        • Gonenc A.
        • Akmer M.
        • Torun M.
        Lipid peroxidation and total antioxidant status in patients with breast cancer.
        Cell Biochem Func. 2007; 25: 377-382
        • Polat M.F.
        • Taysi S.
        • Gul M.
        • Cikman O.
        • Yilmaz I.
        • Bakan E.
        • et al.
        Oxidant/antioxidant status in blood of patients with malignant breast tumor and benign disease.
        Cell Biochem Func. 2002; 20: 327-331
        • Ray G.
        • Batra S.
        • Shukla N.K.
        • Deo S.
        • Raina V.
        • Ashok S.
        • et al.
        Lipid peroxidation, free radical production and antioxidant status in breast cancer.
        Breast Cancer Res Treat. 2000; 59: 163-170
        • Dreher D.
        Role of oxygen free radicals in cancer development.
        Eur J Cancer. 1996; 32: 30-38
        • Renschler M.F.
        The emerging role of reactive oxygen species in cancer therapy.
        Eur J Cancer. 2004; 40: 1934-1940
        • Kong Q.
        • Lillehei K.O.
        Antioxidant inhibitors for cancer therapy.
        Med Hypothesis. 1998; 51: 405-409
        • Kong Q.
        • Beel J.A.
        • Lillehei K.O.
        A threshold concept for cancer therapy.
        Med Hypothesis. 2000; 55: 29-35
        • Lopez-Lazaro M.
        Dual role of hydrogen peroxide in cancer: Possible relevance to cancer chemoprevention and therapy.
        Cancer Lett. 2007; 252: 1-8
        • McCarty M.F.
        • Barraso-Aranda J.
        • Contreras F.
        A two phase strategy for treatment of oxidant dependent cancers.
        Med Hypothesis. 2007; 69: 489-496
        • Nicco C.
        • Laurent A.
        • Chereau C.
        • Weill B.
        • Batteux F.
        Differential modulation of normal and tumor cell proliferation by reactive oxygen species.
        Biomed Pharmacother. 2005; 59: 169-174
        • Green H.N.
        Hydrogen peroxide and tumour therapy.
        Nature. 1958; 181: 128-129
        • Sugiura K.
        Effect of hydrogen peroxide on transplanted rat and mouse tumors.
        Nature. 1958; 182: 1310-1311
        • Fang J.
        • Nakamura H.
        • Iyer A.K.
        Tumor-targeted induction of oxystress for cancer therapy.
        J Drug Targ. 2007; 15: 475-486
        • Nathan C.F.
        • Cohn Z.A.
        Anti-tumor effects of hydrogen peroxide in-vivo.
        J Exp Med. 1981; 1254: 1539-1553
        • Ben-Yoseph O.
        • Ross B.D.
        Oxidation therapy: the use of a reactive oxygen species-generating enzyme system for tumour treatment.
        Br J Cancer. 1994; 70: 1131-1135
        • Simizu S.
        • Umezawa K.
        • Imoto M.
        Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs.
        J Biol Chem. 1998; 273: 26900-26907
        • Alexandre J.
        • Batteux F.
        • Nicco C.
        • Chereau C.
        • Laurent A.
        • Guillevin L.
        • et al.
        Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo.
        Int J Cancer. 2006; 119: 41-48
        • Yoshikawa T.
        • Tainaka K.
        • Naito Y.
        • Kondo M.
        A novel cancer therapy based on oxygen radicals.
        Cancer Res. 1995; 55: 1617-1620
        • Berneis K.
        • Bollag W.
        • Kaiser A.
        • Langmann A.
        The degradation of deoxyribonucleic acid by new tumour inhibiting compounds: the intermediate formation of hydrogen peroxide.
        Experientia. 1963; 19: 132-133
        • Skapek S.X.
        • Colvin O.M.
        • Griffith O.W.
        • Elion G.B.
        • Bigner D.D.
        • Friedman H.S.
        Enhanced melphalan cytotoxicity following buthionine sulfoximine-mediated glutathione depletion in a human medulloblastoma xenograft in athymic mice.
        Cancer Res. 1988; 48: 2764-2767
        • Ramanathan B.
        • Jan K.-Y.
        • Chen C.-H.
        • Hour T.-C.
        • Yu H.-Y.
        • Pu Y.-S.
        Resistance to paclitaxel is proportional to cellular total antioxidant capacity.
        Cancer Res. 2005; 65: 8455-8460
        • Bailey H.H.
        • Ripple G.
        • Tutsch K.D.
        • Arzoomanian R.Z.
        • Alberti D.
        • Feierabend C.
        • et al.
        Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan.
        J Natl Cancer Inst. 1997; 89: 1789-1796
        • Maeda H.
        • Hori S.
        • Ohizumi H.
        • Segawa T.
        • Kakehi Y.
        • Ogawa O.
        • et al.
        Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine.
        Cell Death Differ. 2004; 11: 737-746
        • Chen G.Q.
        • Tang W.
        • Xiong S.M.
        • Zhu J.
        • Cai X.
        • Han Z.G.
        • et al.
        Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I As2O3 exerts dose-dependent dual effects on APL cells..
        Blood. 1993; 89: 3345-3353
        • Shen Z.X.
        • Ni C.G.
        • Li J.H.
        • Xiong X.S.
        • Qiu S.M.
        • Zhu Q.Y.
        • et al.
        Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II Clinical efficacy and pharmacokinetics in relapsed patients..
        Blood. 1997; 89: 3354-3360
        • Forouzannia A.
        • Khuntia D.
        • Mehta M.P.
        Motexafin gadolinium: a novel radiosensitizer for brain tumors.
        Expert Rev Anticancer Ther. 2007; 7: 785-796
        • Magda D.
        • Miller R.A.
        Motexafin gadolinium: A novel redox active drug for cancer therapy.
        Sem Cancer Biol. 2006; 16: 466-476
        • Richards G.M.
        • Mehta M.P.
        Motexafin gadolinium in the treatment of brain metastases.
        Expert Opin Pharmacother. 2007; 8: 351-359
        • Walshe J.M.
        Penicillamine, a new oral therapy for Wilson’s disease.
        Am J Med. 1956; 21: 487-495
        • Joyce D.A.
        d-penicillamine pharmacokinetics and pharmacodynamics in man.
        Pharmc Ther. 1989; 42: 405-427
        • Goonerante S.R.
        • Christensen D.A.
        Effect of chelating agents on the excretion of copper, zinc and iron in the bile and urine of sheep.
        Vet J. 1997; 153: 171-178
        • Matasubara T.
        • Saura R.
        • Hirohata K.
        • Ziff M.
        Inhibition of Human Endothelial cell proliferation in vitro and neovascularization in vivo by d-penicillamine.
        J Clin Inves. 1989; 83: 158-167
        • Yoshida D.
        • Ikeda Y.
        • Nakazawa S.
        Suppression of 9L gliosarcoma growth by copper depletion with copper deficient diet and d-penicillamine.
        J Neuro-Oncol. 1993; 17: 91-97
        • Hourani B.T.
        • Demopoulos H.B.
        Inhibition of S-91 mouse melanoma metastases and growth by d-penicillamine.
        Lab Inves. 1969; 21: 434-438
        • Gross J.L.
        • Herblin W.F.
        Inhibition of basic fibroblast growth factor-induced angiogenesis and glioma tumor growth in vivo in copper depleted rats.
        Proc Annu Meet Am Assoc Cancer Res. 1991; 32: 338
        • Starkebaum G.
        • Root R.K.
        d-penicillamine: analysis of the mechanism of copper catalyzed hydrogen peroxide generation.
        J Imm. 1985; 134: 3371-3378
        • Gupte A.
        • Mumper R.J.
        An investigation into copper catalyzed d-penicillamine oxidation and subsequent hydrogen peroxide generation.
        J Inorg Biochem. 2007; 101: 594-602
        • Huang Y-L.
        • Sheu J.H.
        • Lin T-H.
        Association between oxidative stress and changes of trace elements in patients with breast cancer.
        Clin Biochem. 1999; 32: 131-136
        • Cohen Y.
        • Epelbaum R.
        • Haim N.
        • Mcshan D.
        • Zinder O.
        The value of serum copper levels in non-hodgkin’s lymphoma.
        Cancer. 1984; 53: 296-300
        • Yucel I.
        • Arpaci F.
        • Ozet A.
        • Doner B.
        • Karayilanoglu T.
        • Sayar A.
        • et al.
        Serum copper and zinc and copper/zinc ratio in patients with breast cancer.
        Biol Trace Elem Res. 1994; 40: 31-37
        • Gupta S.K.
        • Shukla V.K.
        • Vaidya M.P.
        • Roy S.K.
        • Gupta S.
        Serum trace elements and Cu/Zn ratio in breast cancer patients.
        J Surg Oncol. 1991; 46: 178-181
        • Sharma K.
        • Mittal D.K.
        • Kesarwani R.C.
        • Kamboj V.P.
        • Chowdrey
        Diagnostic and prognostic significance of serum and tissue trace elements in breast malignancy.
        Ind J Med Sci. 1994; 48: 227-232
        • Rizk S.L.
        • Sky-Peck H.H.
        Comparison between concentrations of trace elements in normal and neoplastic human breast tissue.
        Cancer Res. 1984; 44: 5390-5394
        • Yaman M.
        • Kaya G.
        • Simsek M.
        Comparison of trace element concentrations in cancerous and noncancerous human endometrial and ovary tissues.
        Int J Gyn Cancer. 2007; 17: 200-228
        • Santoliquido P.M.
        • Southwick H.W.
        Trace metal levels in cancer of the breast.
        Sur Gyn Obs. 1976; 142: 65-69
        • Mulay I.L.
        • Roy R.
        • Knox B.E.
        • Suhr N.H.
        Trace metal analysis of cancerous and non-cancerous human tissues.
        J Natl Cancer Ins. 1971; 47: 1-13
        • Yaman M.
        • Kaya G.
        • Yekeler H.
        Distribution of trace metal concentrations in paired cancerous and non-cancerous human stomach tissues.
        World J Gastr. 2007; 13: 612-618
        • Seifried H.E.
        • Anderson D.E.
        • Fisher E.I.
        • Milner J.A.
        A review of the interaction among dietary antioxidants and reactive oxygen species.
        J Nutr Biochem. 2007; 18: 567-579