522
Views
37
CrossRef citations to date
0
Altmetric
Review Article

Glutathione in metastases: From mechanisms to clinical applications

, , , &
Pages 253-267 | Received 11 Aug 2015, Accepted 22 Dec 2015, Published online: 18 Feb 2016

References

  • Sies H. Biochemistry of oxidative stress. Angew Chem Int Ed Eng 1986;25:1058–71
  • Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol 2015;4:180–3
  • Harris IS, Treloar AE, Inoue S, et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 2015;27:211–22
  • Piskounova E, Agathocleous M, Murphy MM, et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015;527:186–91
  • Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983;52:711–60
  • Sies H. Glutathione and its role in cellular functions. Free Radic Biol Med 1999;27:916–21
  • Estrela JM, Ortega A, Obrador E. Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 2006;43:143–81
  • Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 2009;30:1–12
  • Mitchell JB, Russo A. The role of glutathione in radiation and drug induced cytotoxicity. Br J Cancer Suppl 1987;8:96–104
  • Meister A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther 1991;51:155–94
  • Calvert P, Yao KS, Hamilton TC, O'Dwyer PJ. Clinical studies of reversal of drug resistance based on glutathione. Chem Biol Interact 1998;111112:213–24
  • Obrador E, Carretero J, Esteve JM, et al. Glutamine potentiates TNF-alpha-induced tumor cytotoxicity. Free Radic Biol Med 2001;31:642–50
  • Pani G, Galeotti T, Chiarugi P. Metastasis: cancer cell's escape from oxidative stress. Cancer Metastasis Rev 2010;29:351–78
  • Gamcsik MP, Kasibhatla MS, Teeter SD, Colvin OM. Glutathione levels in human tumors. Biomarkers 2012;17:671–91
  • Traverso N, Ricciarelli R, Nitti M, et al. Role of glutathione in cancer progression and chemoresistance. Oxid Med Cell Longev 2013;2013:972913
  • Aquilano K, Baldelli S, Ciriolo MR. Glutathione: new roles in redox signaling for an old antioxidant. Front Pharmacol 2014;5:196
  • Jones DP. Redox potential of GSH/GSSG couple: assay and biological significance. Methods Enzymol 2002;348:93–112
  • Srivastava N, Kollipara RK, Singh DK, et al. Inhibition of cancer cell proliferation by PPARgamma is mediated by a metabolic switch that increases reactive oxygen species levels. Cell Metab 2014;20:650–61
  • Irani K, Xia Y, Zweier JL, et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997;275:1649–52
  • Polytarchou C, Hatziapostolou M, Papadimitriou E. Hydrogen peroxide stimulates proliferation and migration of human prostate cancer cells through activation of activator protein-1 and up-regulation of the heparin affin regulatory peptide gene. J Biol Chem 2005;280:40428–35
  • Marshall HE, Merchant K, Stamler JS. Nitrosation and oxidation in the regulation of gene expression. FASEB J 2000;14:1889–900
  • Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 2004;4:592–603
  • Payne SL, Fogelgren B, Hess AR, et al. Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res 2005;65:11429–36
  • Lamonte G, Tang X, Chen JL, et al. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress. Cancer Metab 2013;1:23
  • Lu J, Tan M, Cai Q. The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett 2015;356:156–64
  • Erickson JW, Cerione RA. Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget 2010;1:734–40
  • Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004;4:891–9
  • Sies H, Gerstenecker C, Menzel H, Flohe L. Oxidation in the NADP system and release of GSSG from hemoglobin-free perfused rat liver during peroxidatic oxidation of glutathione by hydroperoxides. FEBS Lett 1972;27:171–5
  • Dickinson DA, Forman HJ. Glutathione in defense and signaling: lessons from a small thiol. Ann N Y Acad Sci 2002;973:488–504
  • Ballatori N, Krance SM, Marchan R, Hammond CL. Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol Aspects Med 2009;30:13–28
  • Jedlitschky G, Leier I, Buchholz U, et al. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 1994;54:4833–6
  • Muller M, Meijer C, Zaman GJ, et al. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci USA 1994;91:13033–7
  • Leier I, Jedlitschky G, Buchholz U, et al. ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. Biochem J 1996;314:433–7
  • Keppler D, Leier I, Jedlitschky G. Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biol Chem 1997;378:787–91
  • Ballatori N, Krance SM, Notenboom S, et al. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 2009;390:191–214
  • Yap LP, Sancheti H, Ybanez MD, et al. Determination of GSH, GSSG, and GSNO using HPLC with electrochemical detection. Meth Enzymol 2010;473:137–47
  • Lu SC. Glutathione synthesis. Biochim Biophys Acta 2013;1830:3143–53
  • Hanigan MH. Gamma-glutamyl transpeptidase: redox regulation and drug resistance. Adv Cancer Res 2014;122:103–41
  • Obrador E, Carretero J, Ortega A, et al. gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver. Hepatology 2002;35:74–81
  • Deneke SM, Fanburg BL. Regulation of cellular glutathione. Am J Physiol 1989;257:L163–73
  • Curthoys NP, Hughey RP. Characterization and physiological function of rat renal gamma-glutamyltranspeptidase. Enzyme 1979;24:383–403
  • Hanigan MH, Ricketts WA. Extracellular glutathione is a source of cysteine for cells that express gamma-glutamyl transpeptidase. Biochemistry 1993;32:6302–6
  • Meister A. Selective modification of glutathione metabolism. Science 1983;220:472–7
  • Hochwald SN, Harrison LE, Rose DM, et al. gamma-Glutamyl transpeptidase mediation of tumor glutathione utilization in vivo. J Natl Cancer Inst 1996;88:193–7
  • Ortega AL, Mena S, Estrela JM. Glutathione in cancer cell death. Cancers (Basel) 2011;3:1285–310
  • Liu Y, Hyde AS, Simpson MA, Barycki JJ. Emerging regulatory paradigms in glutathione metabolism. Adv Cancer Res 2014;122:69–101
  • Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48–58
  • Klein CA. Selection and adaptation during metastatic cancer progression. Nature 2013;501:365–72
  • Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature 2013;501:355–64
  • Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 2001;30:1191–212
  • Krebs HA, Veech RL. Equilibrium relations between pyridine nucleotides and adenine nucleotides and their roles in the regulation of metabolic processes. Adv Enzyme Regul 1969;7:397–413
  • Bucher T, Brauser B, Conze A, et al. State of oxidation-reduction and state of binding in the cytosolic NADH-system as disclosed by equilibration with extracellular lactate-pyruvate in hemoglobin-free perfused rat liver. Eur J Biochem 1972;27:301–17
  • Sies H, Brigelius R, Wefers H, et al. Cellular redox changes and response to drugs and toxic agents. Fundam Appl Toxicol 1983;3:200–8
  • Schonfeld P, Bohnensack R, Bohme G, Kunz W. Influence of the beta-hydroxybutyrate/acetoacetate ratio on the redox states of mitochondrial NAD(P) and cytochrome c systems, extramitochondrial ATP/ADP ratio and the respiration of isolated liver mitochondria in the resting state. Biomed Biochim Acta 1983;42:3–13
  • Jones DP, Sies H. The Redox Code. Antioxid Redox Signal 2015;23:734–46
  • Allen JF. Control of gene expression by redox potential and the requirement for chloroplast and mitochondrial genomes. J Theor Biol 1993;165:609–31
  • Jones DP. Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 2008;295:C849–68
  • Pedersen SE, Ross EM. Functional activation of beta-adrenergic receptors by thiols in the presence or absence of agonists. J Biol Chem 1985;260:14150–7
  • Tewes F, Bol GF, Brigelius-Flohe R. Thiol modulation inhibits the interleukin (IL)-1-mediated activation of an IL-1 receptor-associated protein kinase and NF-kappa B. Eur J Immunol 1997;27:3015–21
  • Lee SR, Kwon KS, Kim SR, Rhee SG. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 1998;273:15366–72
  • Yu CX, Li S, Whorton AR. Redox regulation of PTEN by S-nitrosothiols. Mol Pharmacol 2005;68:847–54
  • Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 1993;12:2005–15
  • Pognonec P, Kato H, Roeder RG. The helix-loop-helix/leucine repeat transcription factor USF can be functionally regulated in a redox-dependent manner. J Biol Chem 1992;267:24563–7
  • Rainwater R, Parks D, Anderson ME, et al. Role of cysteine residues in regulation of p53 function. Mol Cell Biol 1995;15:3892–903
  • Ahn SG, Thiele DJ. Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 2003;17:516–28
  • Ilbert M, Horst J, Ahrens S, et al. The redox-switch domain of Hsp33 functions as dual stress sensor. Nat Struct Mol Biol 2007;14:556–63
  • Brigelius-Flohe R, Flohe L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxid Redox Signal 2011;15:2335–81
  • Rhee SG, Kang SW, Jeong W, et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol 2005;17:183–9
  • Sies H. Role of metabolic H2O2 generation: redox signaling and oxidative stress. J Biol Chem 2014;289:8735–41
  • Popov D. Protein S-glutathionylation: from current basics to targeted modifications. Arch Physiol Biochem 2014;120:123–30
  • Shelton MD, Chock PB, Mieyal JJ. Glutaredoxin: role in reversible protein s-glutathionylation and regulation of redox signal transduction and protein translocation. Antioxid Redox Signal 2005;7:348–66
  • Holmgren A. Antioxidant function of thioredoxin and glutaredoxin systems. Antioxid Redox Signal 2000;2:811–20
  • Lillig CH, Berndt C, Holmgren A. Glutaredoxin systems. Biochim Biophys Acta 2008;1780:1304–17
  • Beer SM, Taylor ER, Brown SE, et al. Glutaredoxin 2 catalyzes the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins: implications for mitochondrial redox regulation and antioxidant defense. J Biol Chem 2004;279:47939–51
  • Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003;43:233–60
  • Wild AC, Moinova HR, Mulcahy RT. Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 1999;274:33627–36
  • Biswas M, Chan JY. Role of Nrf1 in antioxidant response element-mediated gene expression and beyond. Toxicol Appl Pharmacol 2010;244:16–20
  • Rotblat B, Melino G, Knight RA. NRF2 and p53: Januses in cancer? Oncotarget 2012;3:1272–83
  • Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 2013;1:45–9
  • Faraonio R, Vergara P, Di Marzo D, et al. p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 2006;281:39776–84
  • Kalechman Y, Strassmann G, Albeck M, Sredni B. Up-regulation by ammonium trichloro(dioxoethylene-0,0′) tellurate (AS101) of Fas/Apo-1 expression on B16 melanoma cells: implications for the antitumor effects of AS101. J Immunol 1998;161:3536–42
  • Muller PA, Vousden KH, Norman JC. p53 and its mutants in tumor cell migration and invasion. J Cell Biol 2011;192:209–18
  • Obrador E, Valles SL, Benlloch M, et al. Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity. PLoS One 2014;9:e96466
  • Bignold LP, Coghlan BL, Jersmann HP. Cancer morphology, carcinogenesis and genetic instability: a background. EXS 2006;96:1–24
  • Scheel C, Onder T, Karnoub A, Weinberg RA. Adaptation versus selection: the origins of metastatic behavior. Cancer Res 2007;67:11476–9
  • Ortega AL, Mena S, Estrela JM. Oxidative and nitrosative stress in the metastatic microenvironment. Cancers (Basel) 2010;2:274–304
  • Nicolson GL. Generation of phenotypic diversity and progression in metastatic tumor cells. Cancer Metastasis Rev 1984;3:25–42
  • Minna JD, Kurie JM, Jacks T. A big step in the study of small cell lung cancer. Cancer Cell 2003;4:163–6
  • Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 2011;21:139–46
  • Talmadge JE, Wolman SR, Fidler IJ. Evidence for the clonal origin of spontaneous metastases. Science 1982;217:361–3
  • Fidler IJ, Talmadge JE. Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Res 1986;46:5167–71
  • Fazilaty H, Gardaneh M, Bahrami T, et al. Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? Tumour Biol 2013;34:2019–30
  • Dawood S, Austin L, Cristofanilli M. Cancer stem cells: implications for cancer therapy. Oncology (Williston Park NY) 2014;28:1101–7
  • Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704–15
  • Morel AP, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008;3:e2888
  • Naka K, Muraguchi T, Hoshii T, Hirao A. Regulation of reactive oxygen species and genomic stability in hematopoietic stem cells. Antioxid Redox Signal 2008;10:1883–94
  • Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 2009;458:780–3
  • Wu WJ, Zhang Y, Zeng ZL, et al. β-Phenylethyl isothiocyanate reverses platinum resistance by a GSH-dependent mechanism in cancer cells with epithelial-mesenchymal transition phenotype. Biochem Pharmacol 2013;85:486–96
  • Zhan Q, Wang C, Ngai S. Ovarian cancer stem cells: a new target for cancer therapy. Biomed Res Int 2013;2013:916819
  • Goto M, Miwa H, Suganuma K, et al. Adaptation of leukemia cells to hypoxic condition through switching the energy metabolism or avoiding the oxidative stress. BMC Cancer 2014;14:76
  • Kim JK, Jeon HY, Kim H. The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. Arch Pharm Res 2015;38:389–401
  • Mena S, Benlloch M, Ortega A, et al. Bcl-2 and glutathione depletion sensitizes B16 melanoma to combination therapy and eliminates metastatic disease. Clin Cancer Res 2007;13:2658–66
  • Diaz LA, Jr Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012;486:537–40
  • Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013;501:328–37
  • Bardelli A, Janne PA. The road to resistance: EGFR mutation and cetuximab. Nat Med 2012;18:199–200
  • Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009;9:274–84
  • Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989;8:98–101
  • Husemann Y, Geigl JB, Schubert F, et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008;13:58–68
  • Guise T. Examining the metastatic niche: targeting the microenvironment. Semin Oncol 2010;37(Suppl 2):S2–14
  • Ordonez-Moran P, Huelsken J. Complex metastatic niches: already a target for therapy? Curr Opin Cell Biol 2014;31:29–38
  • Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer 2009;9:239–52
  • Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 2014;14:611–22
  • Havard M, Dautry F, Tchenio T. A dormant state modulated by osmotic pressure controls clonogenicity of prostate cancer cells. J Biol Chem 2011;286:44177–86
  • Nishikawa S, Ishii H, Haraguchi N, et al. Genotoxic therapy stimulates error-prone DNA repair in dormant hepatocellular cancer stem cells. Exp Ther Med 2012;3:959–62
  • Vincent Z, Urakami K, Maruyama K, et al. CD133-positive cancer stem cells from Colo205 human colon adenocarcinoma cell line show resistance to chemotherapy and display a specific metabolomic profile. Genes Cancer 2014;5:250–60
  • Langley RR, Fidler IJ. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev 2007;28:297–321
  • Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med 2014;7:1–11
  • Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2:563–72
  • Meng S, Tripathy D, Frenkel EP, et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004;10:8152–62
  • Glaves D. Intravascular death of disseminated cancer cells mediated by superoxide anion. Invas Metastasis 1986;6:101–11
  • Bouwens L, Jacobs R, Remels L, Wisse E. Natural cytotoxicity of rat hepatic natural killer cells and macrophages against a syngeneic colon adenocarcinoma. Cancer Immunol Immunother 1988;27:137–41
  • Weiss L, Nannmark U, Johansson BR, Bagge U. Lethal deformation of cancer cells in the microcirculation: a potential rate regulator of hematogenous metastasis. Int J Cancer 1992;50:103–7
  • Barbera-Guillem E, Smith I, Weiss L. Cancer-cell traffic in the liver. II. Arrest, transit and death of B16F10 and M5076 cells in the sinusoids. Int J Cancer 1993;53:298–301
  • Carretero J, Obrador E, Esteve JM, et al. Tumoricidal activity of endothelial cells. Inhibition of endothelial nitric oxide production abrogates tumor cytotoxicity induced by hepatic sinusoidal endothelium in response to B16 melanoma adhesion in vitro. J Biol Chem 2001;276:25775–82
  • Al-Mehdi AB, Tozawa K, Fisher AB, et al. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 2000;6:100–2
  • Radomski MW, Jenkins DC, Holmes L, Moncada S. Human colorectal adenocarcinoma cells: differential nitric oxide synthesis determines their ability to aggregate platelets. Cancer Res 1991;51:6073–8
  • Gassmann P, Haier J. The tumor cell-host organ interface in the early onset of metastatic organ colonisation. Clin Exp Metastasis 2008;25:171–81
  • Orr FW, Wang HH, Lafrenie RM, et al. Interactions between cancer cells and the endothelium in metastasis. J Pathol 2000;190:310–29
  • Burdon RH. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 1995;18:775–94
  • Blanchetot C, Boonstra J. The ROS-NOX connection in cancer and angiogenesis. Crit Rev Eukaryot Gene Expr 2008;18:35–45
  • Hancock JT. The role of redox mechanisms in cell signalling. Mol Biotechnol 2009;43:162–6
  • Nishikawa M. Reactive oxygen species in tumor metastasis. Cancer Lett 2008;266:53–9
  • Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer 2006;6:521–34
  • Chambers AF, MacDonald IC, Schmidt EE, et al. Steps in tumor metastasis: new concepts from intravital videomicroscopy. Cancer Metastasis Rev 1995;14:279–301
  • Yasuda H. Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. Nitric Oxide 2008;19:205–16
  • Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:1582–4
  • Rak J, Mitsuhashi Y, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995;55:4575–80
  • Gnarra JR, Zhou S, Merrill MJ, et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc Natl Acad Sci USA 1996;93:10589–94
  • Siemeister G, Weindel K, Mohrs K, et al. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 1996;56:2299–301
  • Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–9
  • Semenza GL. Involvement of hypoxia-inducible factor 1 in human cancer. Intern Med 2002;41:79–83
  • Meier B, Radeke HH, Selle S, et al. Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumour necrosis factor-alpha. Biochem J 1989;263:539–45
  • Qiu H, Orr FW, Jensen D, et al. Arrest of B16 melanoma cells in the mouse pulmonary microcirculation induces endothelial nitric oxide synthase-dependent nitric oxide release that is cytotoxic to the tumor cells. Am J Pathol 2003;162:403–12
  • Jessup JM, Battle P, Waller H, et al. Reactive nitrogen and oxygen radicals formed during hepatic ischemia-reperfusion kill weakly metastatic colorectal cancer cells. Cancer Res 1999;59:1825–9
  • Anasagasti MJ, Martin JJ, Mendoza L, et al. Glutathione protects metastatic melanoma cells against oxidative stress in the murine hepatic microvasculature. Hepatology 1998;27:1249–56
  • Ortega AL, Carretero J, Obrador E, et al. Tumor cytotoxicity by endothelial cells. Impairment of the mitochondrial system for glutathione uptake in mouse B16 melanoma cells that survive after in vitro interaction with the hepatic sinusoidal endothelium. J Biol Chem 2003;278:13888–97
  • Andreassen K, Mortensen B, Winberg JO, Huseby NE. Increased resistance towards oxidative stress accompanies enhancement of metastatic potential obtained by repeated in vivo passage of colon carcinoma cells in syngeneic rats. Clin Exp Metastasis 2002;19:623–9
  • Bilbao P, del Olmo M, Alonso-Varona A, et al. L2-Oxothiazolidine-4-carboxylate reverses the tumour growth-promoting effect of interleukin-2 and improves the anti-tumour efficacy of biochemotherapy in mice bearing B16 melanoma liver metastases. Melanoma Res 2002;12:17–26
  • Yu YP, Yu G, Tseng G, et al. Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. Cancer Res 2007;67:8043–50
  • Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007;87:99–163
  • Bartoli GM, Sies H. Reduced and oxidized glutathione efflux from liver. FEBS Lett 1978;86:89–91
  • Ballatori N, Rebbeor JF. Roles of MRP2 and oatp1 in hepatocellular export of reduced glutathione. Semin Liver Dis 1998;18:377–87
  • Lazar-Molnar E, Hegyesi H, Toth S, Falus A. Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine 2000;12:547–54
  • Obrador E, Benlloch M, Pellicer JA, et al. Intertissue flow of glutathione (GSH) as a tumor growth-promoting mechanism: interleukin 6 induces GSH release from hepatocytes in metastatic B16 melanoma-bearing mice. J Biol Chem 2011;286:15716–27
  • Barton BE. Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes. Expert Opin Ther Targets 2005;9:737–52
  • Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005;41:2502–12
  • Rossi JF, Lu ZY, Jourdan M, Klein B. Interleukin-6 as a therapeutic target. Clin Cancer Res 2015;21:1248–57
  • Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 2010;46:1223–31
  • Emmenegger U, Kerbel RS. Cancer: chemotherapy counteracted. Nature 2010;468:637–8
  • Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Future Oncol 2010;6:1863–81
  • Leibowitz B, Yu J. Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther 2010;9:417–22
  • Sternberg EM. Neural-immune interactions in health and disease. J Clin Invest 1997;100:2641–7
  • Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol 2004;5:617–25
  • Thaker PH, Sood AK. Neuroendocrine influences on cancer biology. Semin Cancer Biol 2008;18:164–70
  • Besedovsky HO, del Rey A, Klusman I, et al. Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J Steroid Biochem Mol Biol 1991;40:613–18
  • Fauci AS. Mechanisms of the immunosuppressive and anti-inflammatory effects of glucocorticosteroids. J Immunopharmacol 1978;1:1–25
  • Bethin KE, Vogt SK, Muglia LJ. Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation. Proc Natl Acad Sci USA 2000;97:9317–22
  • Antoni MH, Lutgendorf SK, Cole SW, et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 2006;6:240–8
  • Yang EV, Kim SJ, Donovan EL, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun 2009;23:267–75
  • Valles SL, Benlloch M, Rodriguez ML, et al. Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism. J Transl Med 2013;11:72
  • Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev 2010;21:77–82
  • Yu C, Yap N, Chen D, Cheng S. Modulation of hormone-dependent transcriptional activity of the glucocorticoid receptor by the tumor suppressor p53. Cancer Lett 1997;116:191–6
  • Sengupta S, Wasylyk B. Physiological and pathological consequences of the interactions of the p53 tumor suppressor with the glucocorticoid, androgen, and estrogen receptors. Ann NY Acad Sci 2004;1024:54–71
  • Hu W, Zhang C, Wu R, et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 2010;107:7455–60
  • Zhao YN, Guo X, Ma ZG, et al. Pro-apoptotic protein BIM in apoptosis of glucocorticoid-sensitive and -resistant acute lymphoblastic leukemia CEM cells. Med Oncol 2011;28:1609–17
  • Li D, Ueta E, Kimura T, et al. Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination. Cancer Sci 2004;95:644–50
  • Ortega A, Ferrer P, Carretero J, et al. Down-regulation of glutathione and Bcl-2 synthesis in mouse B16 melanoma cells avoids their survival during interaction with the vascular endothelium. J Biol Chem 2003;278:39591–9
  • Mena S, Rodriguez ML, Ortega A, et al. Glutathione and Bcl-2 targeting facilitates elimination by chemoradiotherapy of human A375 melanoma xenografts overexpressing bcl-xl, bcl-2, and mcl-1. J Transl Med 2012;10:8
  • Bissell M. Q&A: Mina Bissell on tumors as organs. . Cancer Discov 2013;3:7
  • Voss MJ, Entschladen F. Tumor interactions with soluble factors and the nervous system. Cell Commun Signal 2010;8:21
  • Shibue T, Weinberg RA. Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin Cancer Biol 2011;21:99–106
  • Dethmers JK, Meister A. Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation. Proc Natl Acad Sci USA 1981;78:7492–6
  • Reliene R, Schiestl RH. Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice. Carcinogenesis 2006;27:240–4
  • Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia 2001;15:1633–40
  • Gumireddy K, Li A, Cao L, et al. NOV-002, A glutathione disulfide mimetic, suppresses tumor cell invasion and metastasis. J Carcinog Mutagen 2013;2013:pii:S7-002
  • Trachootham D, Zhou Y, Zhang H, et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 2006;10:241–52
  • Benlloch M, Mena S, Ferrer P, et al. Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. J Biol Chem 2006;281:69–79
  • Min KJ, Jang JH, Lee JT, et al. Glucocorticoid receptor antagonist sensitizes TRAIL-induced apoptosis in renal carcinoma cells through up-regulation of DR5 and down-regulation of c-FLIP(L) and Bcl-2. J Mol Med (Berl) 2012;90:309–19
  • Raj L, Ide T, Gurkar AU, et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 2011;475:231–4
  • Steinbrenner H, Speckmann B, Sies H. Toward understanding success and failures in the use of selenium for cancer prevention. Antioxid Redox Signal 2013;19:181–91
  • Misra S, Boylan M, Selvam A, et al. Redox-active selenium compounds – from toxicity and cell death to cancer treatment. Nutrients 2015;7:3536–56
  • El-Bayoumy K, Sinha R, Richie JP. Jr Forms of selenium in cancer prevention. In: Brigelius-Flohe R, Sies H, eds. Diversity of Selenium Functions in Health and Disease. Boca Raton (FL): CRC Press; 2015:137–55
  • Cheng Y, Sk UH, Zhang Y, et al. Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death. PLoS One 2012;7:e35104
  • Bapat P, Goswami D, Shastri A, et al. A photographic comparison of seleno-trastuzumab, trastuzumab, and selenite on inhibition of the HER2+ human breast cancer cell line BT-474. Proceedings of the 10th International Symposium on Selenium in Biology and Medicine, Berlin, Germany 14–18 September 2013;p S15
  • Hidalgo M, Rodriguez G, Kuhn JG, et al. A Phase I and pharmacological study of the glutamine antagonist acivicin with the amino acid solution aminosyn in patients with advanced solid malignancies. Clin Cancer Res 1998;4:2763–70
  • Jobanputra P, Amarasena R, Maggs F, et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: a case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008;9:48
  • Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2013;12:931–47
  • Redmond SM, Joncourt F, Buser K, et al. Assessment of P-glycoprotein, glutathione-based detoxifying enzymes and O6-alkylguanine-DNA alkyltransferase as potential indicators of constitutive drug resistance in human colorectal tumors. Cancer Res 1991;51:2092–7
  • Berger SJ, Gosky D, Zborowska E, et al. Sensitive enzymatic cycling assay for glutathione: measurements of glutathione content and its modulation by buthionine sulfoximine in vivo and in vitro in human colon cancer. Cancer Res 1994;54:4077–83
  • Sprem M, Babic D, Abramic M, et al. Glutathione and glutathione S-transferases as early markers for ovarian carcinomas: case series. Croat Med J 2001;42:624–9
  • Ferruzzi E, Franceschini R, Cazzolato G, et al. Blood glutathione as a surrogate marker of cancer tissue glutathione S-transferase activity in non-small cell lung cancer and squamous cell carcinoma of the head and neck. Eur J Cancer 2003;39:1019–29
  • Cook JA, Pass HI, Iype SN, et al. Cellular glutathione and thiol measurements from surgically resected human lung tumor and normal lung tissue. Cancer Res 1991;51:4287–94
  • Perry RR, Mazetta JA, Levin M, Barranco SC. Glutathione levels and variability in breast tumors and normal tissue. Cancer 1993;72:783–7
  • Hochwald SN, Rose DM, Brennan MF, Burt ME. Elevation of glutathione and related enzyme activities in high-grade and metastatic extremity soft tissue sarcoma. Ann Surg Oncol 1997;4:303–9

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.