Redox Pathways as a Platform in Drug Development

Chapter

Abstract

Redox homeostasis is frequently aberrantly regulated in human diseases such as cancer and neurological disorders. Partly as a consequence, there is optimism in validating and extending redox controlling pathways as a platform for the discovery/development of drugs, particularly in cancer. As the primary redox buffer, cellular thiols have been variously therapeutically targeted. N-acetylcysteine is the simplest pharmaceutical version of a bioavailable redox equivalent. It has uses in a number of disparate human pathologies. Other agents have redox active centers primarily as a function of nucleophilic centers associated with the variable valence states of sulfur. Redox homeostasis is aberrantly regulated in cancer cells and this has provided an opportunity to advance treatment concepts that attempt to produce a beneficial therapeutic index. A component of the approaches to prevent cancer is based upon the possibility that thiols provide a way of detoxifying environmental electrophiles prior to enacting damage to DNA that could progress a cell towards a cancerous phenotype. Further, therapies designed to enhance myeloproliferation, hematopoietic progenitor cell mobilization and immune response also have a foundation in modulation of redox pathways within the bone marrow compartment. As a consequence of these principles, a number of “redox modulating” drugs are under development and progressing towards FDA review.

Keywords

Chronic Lymphocytic Leukemia Redox Homeostasis Arsenic Trioxide Ethacrynic Acid Diallyl Disulfide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was supported by grants from the National Institutes of Health (ES017453, CA08660 and CA117259) and support from the South Carolina Centers of Excellence program. We thank the Drug Metabolism and Pharmacokinetics and Proteomics Core Facilities at the Medical University of South Carolina. This work was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.

References

  1. Abate C, Patel L, Rauscher FJ 3rd, Curran T (1990) Redox regulation of fos and jun DNA-binding activity in vitro. Science 249:1157PubMedCrossRefGoogle Scholar
  2. Adams GB et al (2006) Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439:599PubMedCrossRefGoogle Scholar
  3. Adler V et al (1999) Regulation of JNK signaling by GSTp. EMBO J 18:1321PubMedCrossRefGoogle Scholar
  4. Akerlund B et al (1996) Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial. Eur J Clin Pharmacol 50:457PubMedCrossRefGoogle Scholar
  5. Aruoma OI, Halliwell B, Hoey BM, Butler J (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 6:593PubMedCrossRefGoogle Scholar
  6. Baldini M, Sacchetti C (1953) Effect of cystine and cysteine on human bone marrow cultured in medium deficient in amino acids. Rev Hematol 8:3PubMedGoogle Scholar
  7. Bertini R et al (1999) Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells. J Exp Med 189:1783PubMedCentralPubMedCrossRefGoogle Scholar
  8. Brock N, Hilgard P, Pohl J, Ormstad K, Orrenius S (1984) Pharmacokinetics and mechanism of action of detoxifying low-molecular-weight thiols. J Cancer Res Clin Oncol 108:87PubMedCrossRefGoogle Scholar
  9. Calvi LM et al (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841PubMedCrossRefGoogle Scholar
  10. Chou WC et al (2004) Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci USA 101:4578PubMedCrossRefGoogle Scholar
  11. Christopherson KW 2nd, Cooper S, Broxmeyer HE (2003) Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood 101:4680PubMedCrossRefGoogle Scholar
  12. Cipolleschi MG, Dello Sbarba P, Olivotto M (1993) The role of hypoxia in the maintenance of hematopoietic stem cells. Blood 82:2031PubMedGoogle Scholar
  13. Clark LC et al (1998) Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 81:730PubMedCrossRefGoogle Scholar
  14. DeNicola GM et al (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106PubMedCentralPubMedCrossRefGoogle Scholar
  15. Dinkova-Kostova AT, Fahey JW, Talalay P (2004) Chemical structures of inducers of nicotinamide quinone oxidoreductase 1 (NQO1). Methods Enzymol 382:423PubMedCrossRefGoogle Scholar
  16. Dominici S et al (1999) Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation. Free Radic Biol Med 27:623PubMedCrossRefGoogle Scholar
  17. Doroshow JH (1983) Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43:460PubMedGoogle Scholar
  18. Drane P, Bravard A, Bouvard V, May E (2001) Reciprocal down-regulation of p53 and SOD2 gene expression-implication in p53 mediated apoptosis. Oncogene 20:430PubMedCrossRefGoogle Scholar
  19. Evens AM, Balasubramanian L, Gordon LI (2005) Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies. Curr Treat Options Oncol 6:289PubMedCrossRefGoogle Scholar
  20. Fawcett H, Mader JS, Robichaud M, Giacomantonio C, Hoskin DW (2005) Contribution of reactive oxygen species and caspase-3 to apoptosis and attenuated ICAM-1 expression by paclitaxel-treated MDA-MB-435 breast carcinoma cells. Int J Oncol 27:1717PubMedGoogle Scholar
  21. Findlay VJ et al (2004) Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. Mol Pharmacol 65:1070PubMedCrossRefGoogle Scholar
  22. Forchhammer K, Leinfelder W, Bock A (1989) Identification of a novel translation factor necessary for the incorporation of selenocysteine into protein. Nature 342:453PubMedCrossRefGoogle Scholar
  23. Gate L, Majumdar RS, Lunk A, Tew KD (2004) Increased myeloproliferation in glutathione S-transferase pi-deficient mice is associated with a deregulation of JNK and Janus kinase/STAT pathways. J Biol Chem 279:8608PubMedCrossRefGoogle Scholar
  24. Gosset P, Wallaert B, Tonnel AB, Fourneau C (1999) Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages. Eur Respir J 14:98PubMedCrossRefGoogle Scholar
  25. Guzman ML et al (2007) Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood 110:4436PubMedCrossRefGoogle Scholar
  26. Hausheer FH et al (1998) Modulation of platinum-induced toxicities and therapeutic index: mechanistic insights and first- and second-generation protecting agents. Semin Oncol 25:584PubMedGoogle Scholar
  27. Hayes JD, McMahon M (2006) The double-edged sword of Nrf2: subversion of redox homeostasis during the evolution of cancer. Mol Cell 21:732PubMedCrossRefGoogle Scholar
  28. Hayes JD, McMahon M (2009) NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34:176PubMedCrossRefGoogle Scholar
  29. Herzenberg LA et al (1997) Glutathione deficiency is associated with impaired survival in HIV disease. Proc Natl Acad Sci USA 94:1967PubMedCrossRefGoogle Scholar
  30. Hondal RJ, Ruggles EL (2011) Differing views of the role of selenium in thioredoxin reductase. Amino Acids 41:73PubMedCentralPubMedCrossRefGoogle Scholar
  31. Hosokawa K et al (2007) Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction. Biochem Biophys Res Commun 363:578PubMedCrossRefGoogle Scholar
  32. Ito K et al (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12:446PubMedCrossRefGoogle Scholar
  33. Iwasaki H, Suda T (2009) Cancer stem cells and their niche. Cancer Sci 100:1166PubMedCrossRefGoogle Scholar
  34. Jang YY, Sharkis SJ (2007) A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110:3056PubMedCrossRefGoogle Scholar
  35. Jeong M et al (2009) Thioredoxin-interacting protein regulates hematopoietic stem cell quiescence and mobilization under stress conditions. J Immunol 183:2495PubMedCrossRefGoogle Scholar
  36. Jin Y et al (2010) Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res 70:2516PubMedCrossRefGoogle Scholar
  37. Jones DP (2008) Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295:C849PubMedCrossRefGoogle Scholar
  38. Kanter MZ (2006) Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning. Am J Health Syst Pharm 63:1821PubMedCrossRefGoogle Scholar
  39. Kelly GS (1998) Clinical applications of N-acetylcysteine. Altern Med Rev 3:114PubMedGoogle Scholar
  40. Khodarev NN, Kataoka Y, Murley JS, Weichselbaum RR, Grdina DJ (2004) Interaction of amifostine and ionizing radiation on transcriptional patterns of apoptotic genes expressed in human microvascular endothelial cells (HMEC). Int J Radiat Oncol Biol Phys 60:553PubMedCrossRefGoogle Scholar
  41. Knight GD, Laubscher KH, Fore ML, Clark DA, Scallen TJ (1994) Vitalethine modulates erythropoiesis and neoplasia. Cancer Res 54:5623PubMedGoogle Scholar
  42. Korst AE, Eeltink CM, Vermorken JB, van der Vijgh WJ (1997) Pharmacokinetics of amifostine and its metabolites in patients. Eur J Cancer 33:1425PubMedCrossRefGoogle Scholar
  43. Koukourakis MI et al (2004) Amifostine induces anaerobic metabolism and hypoxia-inducible factor 1 alpha. Cancer Chemother Pharmacol 53:8PubMedGoogle Scholar
  44. Kryukov GV et al (2003) Characterization of mammalian selenoproteomes. Science 300:1439PubMedCrossRefGoogle Scholar
  45. Levy EJ, Anderson ME, Meister A (1993) Transport of glutathione diethyl ester into human cells. Proc Natl Acad Sci USA 90:9171PubMedCrossRefGoogle Scholar
  46. Li JJ, Oberley LW (1997) Overexpression of manganese-containing superoxide dismutase confers resistance to the cytotoxicity of tumor necrosis factor alpha and/or hyperthermia. Cancer Res 57:1991PubMedGoogle Scholar
  47. List AF et al (1997) Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. Blood 90:3364PubMedGoogle Scholar
  48. List AF, Heaton R, Glinsmann-Gibson B, Capizzi RL (1998) Amifostine stimulates formation of multipotent and erythroid bone marrow progenitors. Leukemia 12:1596PubMedCrossRefGoogle Scholar
  49. Lothrop AP, Ruggles EL, Hondal RJ (2009) No selenium required: reactions catalyzed by mammalian thioredoxin reductase that are independent of a selenocysteine residue. Biochemistry 48:6213PubMedCentralPubMedCrossRefGoogle Scholar
  50. Lyons RM, Wilks ST, Young S, Brown GL (2011) Oral ezatiostat HCl (Telintra(R), TLK199) and idiopathic chronic neutropenia (ICN): a case report of complete response of a patient with G-CSF resistant ICN following teatment with ezatiostat, a glutathione S-transferase P1-1 (GSTP1-1) inhibitor. J Hematol Oncol 4:43PubMedCentralPubMedCrossRefGoogle Scholar
  51. Lyttle MH et al (1994) Glutathione-S-transferase activates novel alkylating agents. J Med Chem 37:1501PubMedCrossRefGoogle Scholar
  52. Mannervik B (1985) The isoenzymes of glutathione transferase. Adv Enzymol Relat Areas Mol Biol 57:357PubMedGoogle Scholar
  53. Marenzi G et al (2006) N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 354:2773PubMedCrossRefGoogle Scholar
  54. Marshall JR (2001) Larry Clark’s legacy: randomized controlled, selenium-based prostate cancer chemoprevention trials. Nutr Cancer 40:74PubMedCrossRefGoogle Scholar
  55. Martin KR, Kari FW, Barrett JC, French JE (2000) N-acetyl-L-cysteine simultaneously increases mitogenesis and suppresses apoptosis in mitogen-stimulated B-lymphocytes from p53 haploinsufficient Tg.AC (v-Ha-ras) mice. In Vitr Mol Toxicol 13(Winter):237PubMedGoogle Scholar
  56. Miseta A, Csutora P (2000) Relationship between the occurrence of cysteine in proteins and the complexity of organisms. Mol Biol Evol 17:1232PubMedCrossRefGoogle Scholar
  57. Morgan AS, Ciaccio PJ, Tew KD, Kauvar LM (1996) Isozyme-specific glutathione S-transferase inhibitors potentiate drug sensitivity in cultured human tumor cell lines. Cancer Chemother Pharmacol 37:363PubMedCrossRefGoogle Scholar
  58. Nakamura H et al (2001) Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis. Proc Natl Acad Sci USA 98:15143PubMedCrossRefGoogle Scholar
  59. Nakamura H, Masutani H, Yodoi J (2002) Redox imbalance and its control in HIV infection. Antioxid Redox Signal 4:455PubMedCrossRefGoogle Scholar
  60. Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, Muldoon LL (2004) Bone marrow chemoprotection without compromise of chemotherapy efficacy in a rat brain tumor model. J Pharmacol Exp Ther 309:594PubMedCrossRefGoogle Scholar
  61. Nie Y, Han YC, Zou YR (2008) CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med 205:777PubMedCentralPubMedCrossRefGoogle Scholar
  62. O’Dwyer PJ et al (1991) Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res 51:6059PubMedGoogle Scholar
  63. O’Shea JJ, Gadina M, Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109(Suppl):S121PubMedCrossRefGoogle Scholar
  64. Palmer LA et al (2007) S-nitrosothiols signal hypoxia-mimetic vascular pathology. J Clin Invest 117:2592PubMedCentralPubMedCrossRefGoogle Scholar
  65. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104:5431PubMedCrossRefGoogle Scholar
  66. Pelicano H et al (2003) Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 278:37832PubMedCrossRefGoogle Scholar
  67. Pendyala L et al (2003) Modulation of plasma thiols and mixed disulfides by BNP7787 in patients receiving paclitaxel/cisplatin therapy. Cancer Chemother Pharmacol 51:376PubMedGoogle Scholar
  68. Peterson JD, Herzenberg LA, Vasquez K, Waltenbaugh C (1998) Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci USA 95:3071PubMedCrossRefGoogle Scholar
  69. Pluquet O et al (2003) The cytoprotective aminothiol WR1065 activates p53 through a non-genotoxic signaling pathway involving c-Jun N-terminal kinase. J Biol Chem 278:11879PubMedCrossRefGoogle Scholar
  70. Rahmani M et al (2005) Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Res 65:2422PubMedCrossRefGoogle Scholar
  71. Raza A et al (2009a) Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome. J Hematol Oncol 2:20PubMedCentralPubMedCrossRefGoogle Scholar
  72. Raza A et al (2009b) Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood 113:6533PubMedCrossRefGoogle Scholar
  73. Raza A et al (2012) A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Cancer 118(8):2138–2147PubMedCrossRefGoogle Scholar
  74. Reinemer P et al (1992) Three-dimensional structure of class pi glutathione S-transferase from human placenta in complex with S-hexylglutathione at 2.8 A resolution. J Mol Biol 227:214PubMedCrossRefGoogle Scholar
  75. Reliene R, Schiestl RH (2006) Antioxidant N-acetyl cysteine reduces incidence and multiplicity of lymphoma in Atm deficient mice. DNA Repair 5:852PubMedCrossRefGoogle Scholar
  76. Ribizzi I, Darnowski JW, Goulette FA, Sertoli MR, Calabresi P (2000) Amifostine cytotoxicity and induction of apoptosis in a human myelodysplastic cell line. Leuk Res 24:519PubMedCrossRefGoogle Scholar
  77. Roberts RL, Aroda VR, Ank BJ (1995) N-acetylcysteine enhances antibody-dependent cellular cytotoxicity in neutrophils and mononuclear cells from healthy adults and human immunodeficiency virus-infected patients. J Infect Dis 172:1492PubMedCrossRefGoogle Scholar
  78. Romano MF et al (1999) Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NF-kappaB/Rel transcription factors. Blood 94:4060PubMedGoogle Scholar
  79. Rosario LA, O’Brien ML, Henderson CJ, Wolf CR, Tew KD (2000) Cellular response to a glutathione S-transferase P1-1 activated prodrug. Mol Pharmacol 58:167PubMedGoogle Scholar
  80. Rosen LS et al (2004) Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies. Clin Cancer Res 10:3689PubMedCrossRefGoogle Scholar
  81. Rovin BH, Dickerson JA, Tan LC, Fassler J (1997) Modulation of IL-1-induced chemokine expression in human mesangial cells through alterations in redox status. Cytokine 9:178PubMedCrossRefGoogle Scholar
  82. Ruscoe JE et al (2001) Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 298:339PubMedGoogle Scholar
  83. Saavedra JE et al (2001) The secondary amine/nitric oxide complex ion R(2)N[N(O)NO](−) as nucleophile and leaving group in S9N)Ar reactions. J Org Chem 66:3090PubMedCrossRefGoogle Scholar
  84. Saavedra JE et al (2006) PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity. J Med Chem 49:1157PubMedCrossRefGoogle Scholar
  85. Sablina AA et al (2005) The antioxidant function of the p53 tumor suppressor. Nat Med 11:1306PubMedCentralPubMedCrossRefGoogle Scholar
  86. Sahaf B, Heydari K, Herzenberg LA (2005) The extracellular microenvironment plays a key role in regulating the redox status of cell surface proteins in HIV-infected subjects. Arch Biochem Biophys 434:26PubMedCrossRefGoogle Scholar
  87. Schanz J et al (2009) Amifostine has the potential to induce haematologic responses and decelerate disease progression in individual patients with low- and intermediate-1-risk myelodysplastic syndromes. Leuk Res 33:1183PubMedCrossRefGoogle Scholar
  88. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7PubMedGoogle Scholar
  89. Shanmugarajah D et al (2009) Analysis of BNP7787 thiol-disulfide exchange reactions in phosphate buffer and human plasma using microscale electrochemical high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 877:857PubMedCrossRefGoogle Scholar
  90. Shaulian E, Karin M (2001) AP-1 in cell proliferation and survival. Oncogene 20:2390PubMedCrossRefGoogle Scholar
  91. Sheehan D, Meade G, Foley VM, Dowd CA (2001) Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 360:1PubMedCrossRefGoogle Scholar
  92. Shen H et al (2001) Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs. J Pharmacol Exp Ther 297:1067PubMedGoogle Scholar
  93. Sinning I et al (1993) Structure determination and refinement of human alpha class glutathione transferase A1–1, and a comparison with the Mu and Pi class enzymes. J Mol Biol 232:192PubMedCrossRefGoogle Scholar
  94. Smith J, Ladi E, Mayer-Proschel M, Noble M (2000) Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci USA 97:10032PubMedCrossRefGoogle Scholar
  95. Songstad J, Pearson RG (1967) Application of the principle of hard and soft acids and bases to organic chemistry. J Am Chem Soc 89:1827CrossRefGoogle Scholar
  96. Songstad J, Pearson RG (1968) Nucleophilic reactivity constants toward methyl iodide and trans-[Pt(py)2Cl2]. J Am Chem Soc 90:319CrossRefGoogle Scholar
  97. Spencer SR, Wilczak CA, Talalay P (1990) Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. Cancer Res 50:7871PubMedGoogle Scholar
  98. Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794PubMedGoogle Scholar
  99. Terada K, Kaziro Y, Satoh T (1997) Ras-dependent activation of c-Jun N-terminal kinase/stress-activated protein kinase in response to interleukin-3 stimulation in hematopoietic BaF3 cells. J Biol Chem 272:4544PubMedCrossRefGoogle Scholar
  100. Tesio M et al (2011) Enhanced c-Met activity promotes G-CSF-induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 117:419PubMedCrossRefGoogle Scholar
  101. Tew KD (1994) Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 54:4313PubMedGoogle Scholar
  102. Tew KD, Kyle G, Johnson A, Wang AL (1985) Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas. Cancer Res 45:2326PubMedGoogle Scholar
  103. Tew KD et al (2011) The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer. Free Radic Biol Med 51:299PubMedCentralPubMedCrossRefGoogle Scholar
  104. Tirouvanziam R, Conrad CK, Bottiglieri T, Herzenberg LA, Moss RB (2006) High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci USA 103:4628PubMedCrossRefGoogle Scholar
  105. Tothova Z et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128:325PubMedCrossRefGoogle Scholar
  106. Townsend DM, Shen H, Staros AL, Gate L, Tew KD (2002) Efficacy of a glutathione S-transferase pi-activated prodrug in platinum-resistant ovarian cancer cells. Mol Cancer Ther 1:1089PubMedGoogle Scholar
  107. Townsend DM et al (2006) A glutathione S-transferase pi-activated prodrug causes kinase activation concurrent with S-glutathionylation of proteins. Mol Pharmacol 69:501PubMedCrossRefGoogle Scholar
  108. Townsend DM, Pazoles CJ, Tew KD (2008) NOV-002, a mimetic of glutathione disulfide. Expert Opin Investig Drugs 17:1075PubMedCrossRefGoogle Scholar
  109. Townsend DM et al (2009) Novel role for glutathione S-transferase pi. Regulator of protein S-Glutathionylation following oxidative and nitrosative stress. J Biol Chem 284:436PubMedCrossRefGoogle Scholar
  110. Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal 10:1343PubMedCrossRefGoogle Scholar
  111. Velu CS, Niture SK, Doneanu CE, Pattabiraman N, Srivenugopal KS (2007) Human p53 is inhibited by glutathionylation of cysteines present in the proximal DNA-binding domain during oxidative stress. Biochemistry 46:7765PubMedCentralPubMedCrossRefGoogle Scholar
  112. Verschraagen M et al (2004) Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects. Biochem Pharmacol 68:493PubMedCrossRefGoogle Scholar
  113. Wessjohann LA, Schneider A, Abbas M, Brandt W (2007) Selenium in chemistry and biochemistry in comparison to sulfur. Biol Chem 388:997PubMedGoogle Scholar
  114. Wilson A et al (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135:1118PubMedCrossRefGoogle Scholar
  115. Wondrak GT (2009) Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid Redox Signal 11:3013PubMedCrossRefGoogle Scholar
  116. Xinhua J (2008) Structure-based design of anticancer prodrug PABA/NO. Drug Des Devel Ther 2:123Google Scholar
  117. Zafarullah M, Li WQ, Sylvester J, Ahmad M (2003) Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 60:6PubMedCrossRefGoogle Scholar
  118. Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P (2003) Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood 101:4098PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Pharmaceutical and Biomedical SciencesMedical University of South CarolinaCharlestonUSA
  2. 2.Departments of Cell and Molecular Pharmacology and Experimental TherapeuticsMedical University of South CarolinaCharlestonUSA

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