Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 1, pp 1–15 | Cite as

Cytoprotective and regulatory functions of glutathione S-transferases in cancer cell proliferation and cell death

Review Article



Glutathione S-transferases (GSTs) family of enzymes is best known for their cytoprotective role and their involvement in the development of anticancer drug resistance. Recently, emergence of non-detoxifying properties of GSTs has provided them with significant biological importance. Addressing the complex interactions of GSTs with regulatory kinases will help in understanding its precise role in tumor pathophysiology and in designing GST-centered anticancer strategies.


We reviewed all published literature addressing the detoxification and regulatory roles of GSTs in the altered biology of cancer and evaluating novel agents targeting GSTs for cancer therapy.


The role of GSTs, especially glutathione S-transferase P1 isoform in tumoral drug resistance, has been the cause of intense debate. GSTs have been demonstrated to interact with different protein partners and modulate signaling pathways that control cell proliferation, differentiation and apoptosis. These specific functions of GSTs could lead to the development of new therapeutic approaches and to the identification of some interesting candidates for preclinical and clinical development. This review focuses on the crucial role played by GSTs in the development of resistance to anticancer agents and the major findings regarding the different modes of action of GSTs to regulate cell signaling.


Glutathione S-transferase Polymorphism Detoxification Signaling Apoptosis 



Glutathione S-transferase




Glutathione S-transferase P1


Multidrug resistance protein


Reactive oxygen species


c-Jun N-terminal kinase

MAP kinase

Mitogen-activated protein kinase


Apoptosis signal-regulating kinase


Protein kinase A


Protein kinase C


Epidermal growth factor receptor


Fanconi anemia group c DNA repair protein




Signal transducer and activator of transcription


1-Cysteine peroxiredoxin


Nitric oxide


Ethacrynic acid


  1. 1.
    Tew KD, Townsend DM (2012) Glutathione S-transferases as determinants of cell survival and death. Antioxid Redox Signal 17:1728–1737PubMedCentralPubMedGoogle Scholar
  2. 2.
    Board PG, Menon D (2013) Glutathione transferases, regulators of cellular metabolism and physiology. Biochim Biophys Acta 1830:3267–3288PubMedGoogle Scholar
  3. 3.
    Hebert H, Jegerschöld C (2007) The structure of membrane associated proteins in eicosanoid and glutathione metabolism as determined by electron crystallography. Curr Opin Struct Biol 17:396–404PubMedGoogle Scholar
  4. 4.
    Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Ann Rev Pharmacol Toxicol 45:51–88Google Scholar
  5. 5.
    Deponte M (2013) Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta 1830:3217–3266PubMedGoogle Scholar
  6. 6.
    Wu B, Dong D (2012) Human cytosolic glutathione transferases: structure, function, and drug discovery. Trends Pharmacol Sci 33:656–668PubMedGoogle Scholar
  7. 7.
    Dourado DF, Fernandes PA, Pedro A, Ramos MJ (2008) Mammalian cytosolic glutathione transferases. Curr Prot Pept Sci 9:325–337Google Scholar
  8. 8.
    Oakley A (2011) Glutathione transferases: a structural perspective. Drug Metab Rev 43:138–151PubMedGoogle Scholar
  9. 9.
    Dourado DF, Fernandes PA, Mannervik B, Ramos MJ (2008) Glutathione transferase: new model for glutathione activation. Chemistry 14:9591–9598PubMedGoogle Scholar
  10. 10.
    Henderson AP, Bleasdale C, Delaney K, Lindstrom AB, Rappaport SM, Waidyanatha S, Watson WP, Golding BT (2005) Evidence for the formation of Michael adducts from reactions of (E, E)-muconaldehyde with glutathione and other thiols. Bioorg Chem 33:363–373PubMedGoogle Scholar
  11. 11.
    Di Pietro G, Magno LA, Rios-Santos F (2010) Glutathione S-transferases: an overview in cancer research. Expert Opin Drug Metab Toxicol 6:153–170PubMedGoogle Scholar
  12. 12.
    Raijmakers MT, Steegers EA, Peters WH (2001) Glutathione S-transferases and thiol concentrations in embryonic and early fetal tissues. Hum Reprod 16:2445–2450PubMedGoogle Scholar
  13. 13.
    Sherratt PJ, Hayes JD (2001) Glutathione S-transferases. In: Ioannides C (ed) Enzyme systems that metabolise drugs and other xenobiotics. Wiley, UK, pp 319–352Google Scholar
  14. 14.
    Rowe JD, Nieves E, Listowsky I (1997) Subunit diversity and tissue distribution of human glutathione S-transferases: interpretations based on electrospray ionization-MS and peptide sequence-specific antisera. Biochem J 325:481–486PubMedCentralPubMedGoogle Scholar
  15. 15.
    Coles BF, Chen G, Kadlubar FF, Radominska-Pandya A (2002) Interindividual variation and organ-specific patterns of glutathione S-transferase alpha, mu, and pi expression in gastrointestinal tract mucosa of normal individuals. Arch Biochem Biophys 403:270–276PubMedGoogle Scholar
  16. 16.
    Schnekenburger M, Morceau F, Henry E, Blasius R, Dicato M, Trentesaux C, Diederich M (2006) Transcriptional and post-transcriptional regulation of glutathione S-transferase P1 expression during butyric acid-induced differentiation of K562 cells. Leuk Res 30:561–568PubMedGoogle Scholar
  17. 17.
    Oguztuzun S, Abu-Hijleh A, Coban T, Bulbul D, Kilic M, Iscan M (2011) GST isoenzymes in matched normal and neoplastic breast tissue. Neoplasma 58:304–310PubMedGoogle Scholar
  18. 18.
    Bostwick DG, Meiers I, Shanks JH (2007) Glutathione S-transferase: differential expression of alpha, mu, and pi isoenzymes in benign prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. Hum Pathol 38:1394–1401PubMedGoogle Scholar
  19. 19.
    Townsend D, Tew K (2003) Cancer drugs, genetic variation and the glutathione S-transferase gene family. Am J Pharmacogenomics 3:157–172PubMedGoogle Scholar
  20. 20.
    Peklak-Scott C, Smitherman PK, Townsend AJ, Morrow CS (2008) Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin. Mol Cancer Ther 7:3247–3255PubMedCentralPubMedGoogle Scholar
  21. 21.
    Kraggerud SM, Oldenburg J, Alnaes GI, Berg M, Kristensen VN, Fossa SD, Lothe RA (2009) Functional glutathione S-transferase genotypes among testicular germ cell tumor survivors: associations with primary and post-chemotherapy tumor histology. Pharmacogenet Genomics 19:751–759PubMedGoogle Scholar
  22. 22.
    Xie P, Liang Y, Liang G, Liu B (2014) Association between GSTP1 Ile105Val polymorphism and glioma risk: a systematic review and meta-analysis. Tumour Biol 35:493–499PubMedGoogle Scholar
  23. 23.
    Yao L, Ji G, Gu A, Zhao P, Liu N (2012) An updated pooled analysis of glutathione S-transferase genotype polymorphisms and risk of adult gliomas. Asian Pac J Cancer Prev 13:157–163PubMedGoogle Scholar
  24. 24.
    Huang G, Mills L, Worth LL (2007) Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells. Mol Cancer Ther 6:1610–1619PubMedGoogle Scholar
  25. 25.
    Lovrić E, Gatalica Z, Eyzaguirre E, Kruslin B (2010) Expression of maspin and glutathionine S-transferase-pi in normal human prostate andprostatic carcinomas. Appl Immunohistochem Mol Morphol 18:429–432PubMedGoogle Scholar
  26. 26.
    Economopoulos KP, Sergentanis TN (2010) GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis. Eur J Cancer 46:1617–1631PubMedGoogle Scholar
  27. 27.
    Ahn J, Gammon MD, Santella RM, Gaudet MM, Britton JA, Teitelbaum SL, Terry MB, Neugut AI, Eng SM, Zhang Y, Garza C, Ambrosone CB (2006) Effects of glutathione S-transferase A1 (GSTA1) genotype and potential modifiers on breast cancer risk. Carcinogenesis 27:1876–1882PubMedGoogle Scholar
  28. 28.
    van Nguyen T, Janssen MJ, van Oijen MGH, Bergevoet SM, te Morsche RHM, van Asten HAGH, Laheij RJF, Peters WHM, Jansen JBMJ (2010) Genetic polymorphisms in GSTA1, GSTP1, GSTT1, and GSTM1 and gastric cancer risk in a Vietnamese population. Oncology Res 18:349–355Google Scholar
  29. 29.
    Maekawa K, Hamaguchi T, Saito Y, Tatewaki N, Kurose K, Kaniwa N, Eguchi Nakajima T, Kato K, Yamada Y, Shimada Y, Yoshida T,Kamatani N, Ura T, Saito M, Muro K, Fuse N, Yoshino T, Doi T, Otsu A, Saijo N, Sawada J, Okuda H, Matsumura Y (2011) Genetic variation and haplotype structures of the glutathione S-transferase genes GSTA1 and GSTA2 in Japanese colorectal cancer patients. Drug Metab Pharmacokinet 26:646–658Google Scholar
  30. 30.
    Martinez V, Kennedy S, Doolan P, Gammell P, Joyce H, Kenny E, Prakash Mehta J, Ryan E, O’Connor R, Crown J, Clynes M, O’Driscoll L (2008) Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue. Breast Cancer Res Treat 110:521–530PubMedGoogle Scholar
  31. 31.
    Carlsten C, Sagoo GS, Frodsham AJ, Burke W, Higgins JP (2008) Glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based systematic HuGE review and meta-analysis. Am J Epidemiol 167:759–774PubMedGoogle Scholar
  32. 32.
    Zhou Y, Zhuang W, Yin YQ, Liu GJ, Wu TX, Yao X, Du L, Wei ML, Wu XT, Wang H (2010) Glutathione S-transferase M1 null genotype associated with gastric cancer among Asians. Dig Dis Sci 55:1824–1830PubMedGoogle Scholar
  33. 33.
    Gao L-B, Pan X-M, Li L-J, Liang W-B, Bai P, Rao L, Su X-W, Wang T, Zhou B, Wei Y-G, Zhang L (2011) Null genotypes of GSTM1 and GSTT1 contribute to risk of cervical neoplasia: an evidence-based meta-analysis. PLoS ONE 6:e20157PubMedCentralPubMedGoogle Scholar
  34. 34.
    Weiss JR, Kopecky KJ, Godwin J, Anderson J, Willman CL, Moysich KB, Slovak ML, Hoque A, Ambrosone CB (2006) Glutathione S-transferase (GSTM1, GSTT1 and GSTA1) polymorphisms and outcomes after treatment for acute myeloid leukemia: pharmacogenetics in Southwest Oncology Group (SWOG) clinical trials. Leukemia 20:2169–2171PubMedGoogle Scholar
  35. 35.
    Xu Y, Wang J, Dong W (2014) GSTM3 A/B polymorphism and risk for head and neck cancer: a meta-analysis. PLoS ONE 9:e83851PubMedCentralPubMedGoogle Scholar
  36. 36.
    Fryer AA, Ramsay HM, Lovatt TJ, Jones PW, Hawley CM, Nicol DL, Strange RC, Harden PN (2005) Polymorphisms in glutathione S-transferases and non-melanoma skin cancer risk in Australian renal transplant recipients. Carcinogenesis 26:185–191PubMedGoogle Scholar
  37. 37.
    Zhang Y, Ni Y, Zhang H, Pan Y, Ma J, Wang L (2012) Association between GSTM1 and GSTT1 allelic variants and head and neck squamous cell carcinoma. PLoS ONE 7:e47579PubMedCentralPubMedGoogle Scholar
  38. 38.
    Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB (2007) Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator. Carcinogenesis 28:1455–1462PubMedGoogle Scholar
  39. 39.
    de Aguiar ES, Giacomazzi J, Schmidt AV, Bock H, Saraiva-Pereira ML, Schuler-Faccini L, Duarte Filho D, dos Santos PA, Giugliani R, Caleffi M, Camey SA, Ashton-Prolla P (2012) GSTM1, GSTT1, and GSTP1 polymorphisms, breast cancer risk factors and mammographic density in women submitted to breast cancer screening. Rev Bras Epidemiol 15:246–255PubMedGoogle Scholar
  40. 40.
    Settheetham-Ishida W, Yuenyao P, Kularbkaew C, Settheetham D, Ishida T (2009) Glutathione S-transferase (GSTM1 and GSTT1) polymorphisms in cervical cancer in Northeastern Thailand. Asian Pac J Can Prev 10:365–368Google Scholar
  41. 41.
    Howells RE, Redman CW, Dhar KK, Sarhanis P, Musgrove C, Jones PW, Alldersea J, Fryer AA, Hoban PR, Strange RC (1998) Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer. Clin Cancer Res 4:2439–2445PubMedGoogle Scholar
  42. 42.
    Özten N, Sunguroğlu A, Bosland MC (2012) Variations in glutathione S-transferase genes influence risk of chronic myeloid leukemia. Hematol Oncol 30:150–155PubMedGoogle Scholar
  43. 43.
    Dunna NR, Vure S, Sailaja K, Surekha D, Raghunadharao D, Rajappa S, Vishnupriya S (2013) Deletion of GSTM1 and T1 genes as a risk factor for development of acute leukemia. Asian Pac J Cancer Prev 14:2221–2224PubMedGoogle Scholar
  44. 44.
    Nagle CM, Chenevix-Trench G, Spurdle AB, Webb PM (2007) The role of glutathione S-transferase polymorphisms in ovarian cancer survival. Eur J Cancer 43:283–290PubMedGoogle Scholar
  45. 45.
    Goekkurt E, Hoehn S, Wolschke C, Wittmer C, Stueber C, Hossfeld DK, Stoehlmacher J (2006) Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)-novel predictors for response and survival in gastric cancer patients. Br J Cancer 94:281–286PubMedCentralPubMedGoogle Scholar
  46. 46.
    Ge J, Tian AX, Wang QS, Kong PZ, Yu Y, Li XQ, Cao XC, Feng YM (2013) The GSTP1 105Val allele increases breast cancer risk and aggressiveness but enhances response to cyclophosphamide chemotherapy in North China. PLoS ONE 8:e67589PubMedCentralPubMedGoogle Scholar
  47. 47.
    Voso MT, Hohaus S, Guidi F, Fabiani E, D’Alò F, Groner S, Späth D, Doehner K, Leone G, Doehner H, Schlenk RF (2008) Prognostic role of glutathione S-transferase polymorphisms in acute myeloid leukemia. Leukemia 22:1685–1691PubMedGoogle Scholar
  48. 48.
    Lo HW, Ali-Osman F (2007) Genetic polymorphism and function of glutathione S-transferases in tumor drug resistance. Curr Opin Pharmacol 7:367–374PubMedGoogle Scholar
  49. 49.
    Li J, Bluth MH (2011) Pharmacogenomics of drug metabolizing enzymes and transporters: implications for cancer therapy. Pharmacogenom Personal Med 4:11–33Google Scholar
  50. 50.
    Sau A, Pellizzari Tregno F, Valentino F, Federici G, Caccuri AM (2010) Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys 500:116–122PubMedGoogle Scholar
  51. 51.
    Ahire S, Kothawade V, Singh S (2012) A review of glutathione S-transferase in drug resistance. Int J Univ Pharm Life Sci 2Google Scholar
  52. 52.
    Zeng D-F, Zhang J, Zhu L-D, Kong P-Y, Li J-P, Zhang X, Xu W, Wang J-I, Pen X-G, Wang P, Liu S-H (2014) Analysis of drug resistance-associated proteins expressions of patients with the recurrent of acute leukemia via protein microarray technology. Eur Rev Med Pharmacol Sci 18:537–543PubMedGoogle Scholar
  53. 53.
    Kolwijck E, Zusterzeel PLM, Roelofs HMJ, Hendriks JC, Peters WHM, Massuger LFAG (2009) GSTP1-1 in ovarian cyst fluid and disease outcome of patients with ovarian cancer. Cancer Epidemiol Biomarkers Prev 18:2176–2181PubMedGoogle Scholar
  54. 54.
    Tew KD, Monks A, Barone L, Rosser D, Akerman G, Montali JA, Wheatley JB, Schmidt DE Jr (1996) Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program. Mol Pharm 50:149–159Google Scholar
  55. 55.
    Suk K (2012) Proteomic analysis of glioma chemoresistance. Kyoungho Suk. Curr Neuropharmacol 10:72–79Google Scholar
  56. 56.
    Haas S, Pierl C, Harth V, Pesch B, Rabstein S, Brüning T, Ko Y, Hamann U, Justenhoven C, Brauch H, Fischer HP (2006) Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas. Int J Cancer 119:1785–1791PubMedGoogle Scholar
  57. 57.
    Grimminger PP, Maus MK, Schneider PM, Metzger R, Hölscher AH, Sugita H, Danenberg PV, Alakus H, Brabender J (2012) Glutathione S-transferase P1 (GST-P1) mRNA expression and DNA methylation is involved in the pathogenesis and prognosis of NSCLC. Lung Cancer 78:87–91PubMedGoogle Scholar
  58. 58.
    Tan KL, Jankova L, Chan C, Fung CL, Clarke C, Lin BP, Robertson G, Molloy M, Chapuis PH, Bokey L, Dent OF, Clarke SJ (2011) Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer. Histopathology 59:1057–1070PubMedGoogle Scholar
  59. 59.
    Simic T, Savic-Radojevic A, Pljesa-Ercegovac M, Matic M, Mimic-Oka J (2009) Glutathione S-transferases in kidney and urinary bladder tumors. Nat Rev Urol 6:281–289PubMedGoogle Scholar
  60. 60.
    Soh Y, Goto S, Kitajima M, Moriyama S, Kotera K, Nakayama T, Nakajima H, Kondo T, Ishimaru T (2005) Nuclear localisation of glutathione S-transferase pi is an evaluation factor for drug resistance in gynaecological cancers. Clin Oncol (R Coll Radiol) 17:264–270Google Scholar
  61. 61.
    Huang JX, Li FY, Xiao W, Song ZX, Qian RY, Chen P, Salminen E (2009) Expression of thymidylate synthase d glutathione S-transferase pi in patients with esophageal squamous cell carcinoma. World J Gastroenterol 15:4316–4321PubMedCentralPubMedGoogle Scholar
  62. 62.
    Geng M, Wang L, Chen X, Cao R, Li P (2013) The association between chemosensitivity and Pgp, GST-π and Topo II expression in gastric cancer. Diagn Pathal 8:198Google Scholar
  63. 63.
    Finn NA, Findley HW, Kemp ML (2011) A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. PLoS Comput Biol 7:e1002151PubMedCentralPubMedGoogle Scholar
  64. 64.
    Kanwal R, Pandey M, Bhaskaran N, Maclennan GT, Fu P, Ponsky LE, Gupta S (2014) Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1. Mol Carcinog 53:8–18PubMedCentralPubMedGoogle Scholar
  65. 65.
    Brognard J, Hunter T (2011) Protein kinase signaling networks in cancer. Curr Opin Genet Dev 21:4–11PubMedCentralPubMedGoogle Scholar
  66. 66.
    Ebelt ND, Cantrell MA, van den Berg CL (2013) c-Jun N-terminal kinases mediate a wide range of targets in the metastatic cascade. Genes Cancer 4:378–387PubMedCentralPubMedGoogle Scholar
  67. 67.
    Tournier C (2013) The 2 faces of JNK signaling in cancer. Genes Cancer 4:397–400PubMedCentralPubMedGoogle Scholar
  68. 68.
    Adler V, Yin Z, Fuchs SY, Benerza M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR, Davis RJ, Ronai Z (1999) Regulation of JNK signaling by GSTp. EMBO J 18:1321–1334PubMedCentralPubMedGoogle Scholar
  69. 69.
    Yin Z, Ivanov V, Habelhah H, Tew KD, Ronai Z (2002) Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res 60:4053–4057Google Scholar
  70. 70.
    Bernardini S, Bellincampi L, Ballerini S, Ranalli M, Pastrol A, Cortese C, Federici G (2002) Role of GST P1-1 in mediating the effect of etoposide on human neuroblastoma cell line Sh-Sy5y. J Cell Biochem 86:340–347PubMedGoogle Scholar
  71. 71.
    Chen N, She Q, Bode AM, Dong Z (2002) Differential gene expression profiles of Jnk1- and Jnk2-deficient murine fibroblast cells. Cancer Res 62:1300–1304PubMedGoogle Scholar
  72. 72.
    Bubici C, Papa S (2014) JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 171:24–37PubMedGoogle Scholar
  73. 73.
    Sau A, Filomeni G, Pezzola S, D’Aguanno S, Tregno FP, Urbani A, Serra M, Pasello M, Picci P, Federici G, Caccuri AM (2012) Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines. Mol BioSyst 8:994–1006PubMedGoogle Scholar
  74. 74.
    Yang Y, Chang J-Z, Singhal SS, Saini M, Pandaya U, Awasthi S, Awasthi YC (2001) Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem 276:19220–19230PubMedGoogle Scholar
  75. 75.
    Cheng J-Z, Singhal SS, Sharma A, Saini M, Yang Y, Awasthi S, Zimniak P, Awasthi YC (2001) Transfection of mGSTA4 in HL-60 cells protects against 4-hydroxynonenal-induced apoptosis by inhibiting JNK-mediated signaling. Arch Biochem Biophys 392:197–207PubMedGoogle Scholar
  76. 76.
    Romero L, Andrews K, Lorraine NG, O’Rourke K, Maslem A, Kirby G (2006) Human GSTA1-1 reduces c-Jun N-terminal kinase signalling and apoptosis in Caco-2 cells. Biochem J 400:135–141PubMedCentralPubMedGoogle Scholar
  77. 77.
    Shiizaki S, Naguro I, Ichijo H (2013) Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling Adv Biol Regul 53:135–144Google Scholar
  78. 78.
    Cho SG, Lee YH, Park HS, Ryoo K, Kang KW, Park J, Eom SJ, Kim MJ, Chang TS, Choi SY, Shim J, Kim Y, Dong MS, Lee MJ, Kim SG, Ichijo H, Choi EJ (2001) Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1. J Biol Chem 276:12749–12755PubMedGoogle Scholar
  79. 79.
    Dorion S, Lambert H, Landry J (2002) Activation of the p38 signaling pathway by heat shock involves the dissociation of glutathione S-transferase Mu from Ask1. J Biol Chem 34:30792–30797Google Scholar
  80. 80.
    Wu Y, Fan Y, Xue B, Luo L, Shen J, Zhang S, Jiang Y, Yin Z (2006) Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals. Oncogene 25:5787–5800PubMedGoogle Scholar
  81. 81.
    Lo H-W, Antoun GR, Ali-Osman F (2004) The human glutathione S-transferase P1 protein is phosphorylated and its metabolic function enhanced by the Ser/Thr protein kinases, cAMPdependent protein kinase and protein kinase C, in glioblastoma cells. Cancer Res 64:9131–9138PubMedGoogle Scholar
  82. 82.
    Okamura T, Singh S, Buolamwini J, Haystead T, Friedman H, Bigner D, Ali-Osman F (2009) Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor. J Biol Chem 284:16979–16989PubMedCentralPubMedGoogle Scholar
  83. 83.
    Singh S, Okamura T, Ali-Osman F (2009) Serine phosphorylation of glutathione S-transferase P1 (GSTP1) by PKCα enhances GSTP1-dependent cisplatin metabolism and resistance in human glioma cells. Biochem Pharmacol 80:1343–1355Google Scholar
  84. 84.
    Pagano G, Youssoufian H (2003) Fanconi anaemia proteins: major roles in cell protection against oxidative damage. BioEssays 25:589–595PubMedGoogle Scholar
  85. 85.
    Cumming RC, Lightfoot J, Beard K, Youssoufian H, O’Brien PJ, Buchwald M (2001) Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat Med 7:814–820PubMedGoogle Scholar
  86. 86.
    Koh J, Ali-Osman F (2007) GSTP1 forms a stable, non-covalent complex with the tissue transglutaminase TGM2 in human glioblastoma cells. Proc Annu Meet Am Assoc Cancer Res 98:4488Google Scholar
  87. 87.
    Kamran MZ, Patil P, Gude RP (2013) Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int 421821Google Scholar
  88. 88.
    Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR (2013) STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci USA 110:16975–16980PubMedCentralPubMedGoogle Scholar
  89. 89.
    Kou X, Chen N, Feng Z, Luo L, Yin Z (2013) GSTP1 negatively regulates Stat3 activation in epidermal growth factor signaling. Oncol Lett 5:1053–1057PubMedCentralPubMedGoogle Scholar
  90. 90.
    Pastore A, Piemonte F (2012) S-Glutathionylation signaling in cell biology: progress and prospects. Eur J Pharm Sci 46:279–292PubMedGoogle Scholar
  91. 91.
    Townsend DM, Manevich Y, He L, Hutchens S, Pazoles CJ, Tew KD (2009) Novel role for glutathione S-transferase pi. Regulator of protein S-glutathionylation following oxidative and nitrosative stress. J Biol Chem 284:436–445PubMedCentralPubMedGoogle Scholar
  92. 92.
    Nevalainen TJ (2010) 1-Cysteine peroxiredoxin: a dual-function enzyme with peroxidase and acidic Ca2 + -independent phospholipase A2 activities. Biochimie 92:638–644PubMedGoogle Scholar
  93. 93.
    Neumann CA, Cao J, Manevich Y (2009) Peroxiredoxin 1 and its role in cell signaling. Cell Cycle 8:4072–4078PubMedGoogle Scholar
  94. 94.
    Ralat LA, Misquitta SA, Manevich Y, Fisher AB, Colman RF (2008) Characterization of the complex of glutathione S-transferase pi and 1-cysteine peroxiredoxin. Arch Biochem Biophys 474:109–118PubMedGoogle Scholar
  95. 95.
    Manevich Y, Feinstein SI, Fisher AB (2004) Activation of the antioxidant enzyme 1-CYS peroxiredoxin requires glutathionylation mediated by heterodimerization with πGST. Proc Natl Acad Sci USA 101:3780–3785PubMedCentralPubMedGoogle Scholar
  96. 96.
    Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG (2002) The role of nitric oxide in cancer. Cell Res 12:311–320PubMedGoogle Scholar
  97. 97.
    Richardson DR, Lok HC (2008) The nitric oxide-iron interplay in mammalian cells: transport and storage of dinitrosyl iron complexes. Biochim Biophys Acta 1780:638–651PubMedGoogle Scholar
  98. 98.
    Singh S, Gupta AK (2011) Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies. Cancer Chemother Pharmacol 67:1211–1224PubMedGoogle Scholar
  99. 99.
    Pedersen JZ, De Maria F, Turella P, Federici G, Mattei M, Fabrini R, Dawood KF, Massimi M, Caccuri AM, Ricci G (2007) Glutathione transferases sequester toxic dinitrosyl-iron complexes in cells: a protection mechanism against excess nitric oxide. J Biol Chem 282:6364–6371PubMedGoogle Scholar
  100. 100.
    Lok HC, Suryo Rahmanto Y, Hawkins CL, Kalinowski DS, Morrow CS, Townsend AJ, Ponka P, Richardson DR (2012) Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes. J Biol Chem 287:607–618PubMedCentralPubMedGoogle Scholar
  101. 101.
    van Iersel ML, Ploemen JP, Lo Bello M, Federici G, van Bladeren PJ (1997) Interactions of alpha, beta-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact 108:67–78PubMedGoogle Scholar
  102. 102.
    Tirona RG, Pang KS (1999) Bimolecular glutathione conjugation kinetics of ethacrynic acid in rat liver: in vitro and perfusion studies. J Pharmacol Exp Ther 290:1230–1241PubMedGoogle Scholar
  103. 103.
    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 37:363–370PubMedGoogle Scholar
  104. 104.
    Johansson K, Ito M, Schophuizen CM, Mathew Thengumtharayil S, Heuser VD, Zhang J, Shimoji M, Vahter M, Ang WH, Dyson PJ, Shibata A, Shuto S, Ito Y, Abe H, Morgenstern R (2011) Characterization of new potential anticancer drugs designed to overcome glutathione transferase mediated resistance. Mol Pharm 8:1698–1708PubMedGoogle Scholar
  105. 105.
    Rodriguez-Vicente J, Vicente-Ortega V, Canteras-Jordana M (1998) The effects of different antineoplastic agents and of pretreatment by modulators on three melanoma lines. Cancer 82:495–502PubMedGoogle Scholar
  106. 106.
    Zhang P, Chen JH, Dong X, Tang MT, Gao LY, Zhao GS, Yu LG, Guo XL (2013) 6r, a novel oxadiazole analogue of ethacrynic acid, exhibits antitumor activity both in vitro and in vivo by induction of cell apoptosis and S-phase arrest. Biomed Pharmacother 67:58–65PubMedGoogle Scholar
  107. 107.
    O’Dwyer PJ, LaCreta F, Nash S, Tinsley PW, Schilder R, Clapper ML, Tew KD, Panting L, Litwin S, Comis RL (1991) Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res 51:6059–6065PubMedGoogle Scholar
  108. 108.
    Hamilton D, Batist G (2005) TLK-199 (Telik). IDrugs 8:662–669PubMedGoogle Scholar
  109. 109.
    O’Brien ML, Vulevic B, Freer S, Boyd J, Shen H, Tew KD (1999) Glutathione peptidomimetic drug modulator of multidrug resistance-associated protein. J Pharmacol Exp Ther 291:1348–1355PubMedGoogle Scholar
  110. 110.
    Raza A, Galili N, Callander N, Ochoa L, Piro L, Emanuel P, Williams S, Burris H, Faderl S, Estrov Z, Curtin P, Larson RA, Keck JG, Jones M, Meng L, Brown GL (2009) 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 2:20PubMedCentralPubMedGoogle Scholar
  111. 111.
    Ruscoe JE, Rosario LA, Wang T, Gaté L, Arifoglu P, Wolf CR, Henderson CJ, Ronai Z, Tew KD (2001) Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 298:339–345PubMedGoogle Scholar
  112. 112.
    Tew KD (2005) TLK-286: a novel glutathione S-transferase-activated prodrug. Expert Opin Investig Drugs 14:1047–1054PubMedGoogle Scholar
  113. 113.
    Dourado DFAR, Fernandes PA, Ramos MJ, Mannervik B (2013) Mechanism of glutathione transferase P1-1-catalyzed activation of the prodrug canfosfamide (TLK286, TELCYTA). Biochemistry 52:8069–8078PubMedGoogle Scholar
  114. 114.
    Xu H, Namgoong S-Y, Roth E, Brown GL, Keck JG (2004) Synergistic effect of TELCYTA™ (TLK286) in combination with paclitaxel, doxorubicin, carboplatin, oxaliplatin, cisplatin, docetaxel, gemcitabine and iressa in human cancer cells. Proc Amer Assoc Cancer Res 45, Abstract #2008Google Scholar
  115. 115.
    Izbicka E, Lawrence R, Cerna C, Von Hoff DD, Sanderson PE (1997) Activity of TER286 against human tumor colony-forming units. Anticancer Drugs 8:345–348PubMedGoogle Scholar
  116. 116.
    Morgan AS, Sanderson PE, Borch RF, Tew KD, Niitsu Y, Takayama T, Von Hoff DD, Izbicka E, Mangold G, Paul C, Broberg U, Mannervik B, Henner WD, Kauvar LM (1998) Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase. Cancer Res 58:2568–2575PubMedGoogle Scholar
  117. 117.
    Rosen LS, Brown J, Laxa B, Boulos L, Reiswig L, Henner WD, Lum RT, Schow SR, Maack CA, Keck JG, Mascavage JC, Dombroski JA, Gomez RF, Brown GL (2003) Phase I study of TLK286 (glutathione S-transferase P1-1 activated glutathione analogue) in advanced refractory solid malignancies. Clin Cancer Res 9:1628–1638PubMedGoogle Scholar
  118. 118.
    Carboplatin, Paclitaxel and TLK286 (Telcyta) as first-line therapy in advanced non-small cell lung cancer. (Protocol ID: TLK286.2023 NCT00088556) Oct 2013
  119. 119.
    Liu J, Li C, Qu W, Leslie E, Bonifant CL, Buzard GS, Saavedra JE, Keefer LK, Waalkes MP (2004) Nitric oxide prodrugs and metallochemotherapeutics: JS-K and CB-3-100 enhance arsenic and cisplatin cytolethality by increasing cellular accumulation. Mol Cancer Ther 3:709–714PubMedGoogle Scholar
  120. 120.
    Saavedra JE, Srinivasan A, Buzard GS, Davies KM, Waterhouse DJ, Inami K, Wilde TC, Citro ML, Cuellar M, Deschamps JR, Parrish D, Shami PJ, Findlay VJ, Townsend DM, Tew KD, Singh S, Jia L, Ji X, Keefer LK (2006) PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity. J Med Chem 49:1157–1164PubMedGoogle Scholar
  121. 121.
    Findlay VJ, Townsend DM, Saavedra JE, Buzard GS, Citro ML, Keefer LK, Ji X, Tew KD (2004) Tumor cell responses to a novel glutathione S-transferase-activated nitric oxide-releasing prodrug. Mol Pharmacol 65:1070–1079PubMedGoogle Scholar
  122. 122.
    Ricci G, De Maria F, Antonini G, Turella P, Bullo A, Stella L, Filomeni G, Federici G, Caccuri AM (2005) 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. J Biol Chem 280:26397–26405PubMedGoogle Scholar
  123. 123.
    Mahajan S, Atkins WM (2005) The chemistry and biology of inhibitors and pro-drugs targeted to glutathione S-transferases. Cell Mol Life Sci 62:1221–1233PubMedGoogle Scholar
  124. 124.
    Müller J, Sidler D, Nachbur U, Wastling J, Brunner T, Hemphill A (2008) Thiazolides inhibit growth and induce glutathione S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells. Int J Cancer 123:1797–1806PubMedGoogle Scholar
  125. 125.
    Zheng J, Liu G, Tozkoparan B, Wen D (2005) Mechanistic studies of inactivation of glutathione S-transferase Pi isozyme by a haloenol lactone derivative. Med Chem 1:191–198PubMedGoogle Scholar
  126. 126.
    Mukanganyama S, Widersten M, Naik YS, Mannervik B, Hasler JA (2002) Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer 97:700–705PubMedGoogle Scholar
  127. 127.
    Lu GD, Shen HM, Chung MC, Ong CN (2007) Critical role of oxidative stress and sustained JNK activation in aloe-emodin-mediated apoptotic cell death in human hepatoma cells. Carcinogenesis 28:1937–1945PubMedGoogle Scholar
  128. 128.
    Aoyama T, Kojima F, Yamazaki T, Tatee T, Abe F, Muraoka Y, Naganawa H, Aoyagi T, Takeuchi T (1993) Benastatins C and D, new inhibitors of glutathione S-transferase, produced by Streptomyces sp. MI384-DF12. Production, isolation, structure determination and biological activities. J Antibiot (Tokyo) 46:712–718Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Biotechnology, School of Engineering and TechnologySharda UniversityGreater NoidaIndia

Personalised recommendations