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Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4

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Abstract

Arsenic trioxide (As2O3) is a highly effective agent in the treatment of acute promyelocytic leukemia (APL), whereas other hematopoietic tumors are less responsive to this agent and mechanisms underlying As2O3,-resistance are poorly understood. To better understand the complex network of GSH-related pathways in As2O3 sensitivity, we investigated the role of GSH and GSH-relevant enzymes in an APL cell line sensitive to As2O3 (NB4) and in a resistant subclone (AsR). Cell proliferation, viability, and apoptosis were investigated in NB4 cells before and after treatment with 1 μM As2O3 and in AsR cells. In these experimental cell models, GSTP1-1, JNK1 and JNK2 proteins were analyzed by immunoblotting, and a kinase assay for JNK1 was performed. GSH levels as well as the activities of the enzymes glutathione peroxidase, glutathione transferase, γ-Glutamylcysteynilsinthetase and superoxide dismutase were measured. NB4 cells treated with As2O3 showed a high level of oxidative stress and an increase of GSH levels. GSTP1-1 polymerization and JNK1 activation were detectable after 24 h and were followed by an increase of the apoptotic rate starting at 72 h. Neither GSTP1-1 polymerization nor JNK activation was found in AsR cells that showed a very low apoptotic rate. Our results suggest that APL sensitivity to As2O3 might be, at least in part, mediated by the balance between association and dissociation of JNK from GSTP1-1, depending on the redox status of the cell. Further investigation is warranted to find a way to interfere with this balance, whenever it might represent a mechanism of drug resistance.

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References

  1. Avvisati G, Lo Coco F, Diverio D et al (1996) AIDA (all-trans retinoic acid+idarubicin) in newly diagnosed acute promyelocitic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) pilot study. Blood 88:1390–1398

    PubMed  CAS  Google Scholar 

  2. Mandelli F, Diverio D, Avvisati G et al (1997) Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-malattie Ematologiche Maligne dell’Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90:1014–1021

    PubMed  CAS  Google Scholar 

  3. Fenaux P, Chastang C, Chevret S et al (1999) A randomized comparison of all-trans retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94:1192–1200

    PubMed  CAS  Google Scholar 

  4. Tallman MS, Andersen JW, Schiffer CA et al (1997) All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021–1028

    Article  PubMed  CAS  Google Scholar 

  5. Mann KK, Shao W, Miller WH Jr (2001) The biology of acute promyelocytic leukemia. Curr Oncol Rep 3:209–216

    Article  PubMed  CAS  Google Scholar 

  6. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY et al (1997) Use of arsenic trioxide in the treatment of acute promyelocitic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360

    PubMed  CAS  Google Scholar 

  7. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E et al (2001) United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852–3860

    PubMed  CAS  Google Scholar 

  8. Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, Han ZG et al (1997) Use of trioxide (As203) in the treatment of acute promyelocytic leukemia. (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89:3345–3353

    PubMed  CAS  Google Scholar 

  9. Miller WH Jr (2002) Molecular targets of arsenic trioxide in malignant cells. Oncologist 7(Suppl 1):14–19

    Article  PubMed  CAS  Google Scholar 

  10. Gao F, Yaun JQ, Shi GY, Tang XM (2004) The cell cycle related apoptotic susceptibility to arsenic trioxide is associated with the level of reactive oxygen species. Cell Res 14(1):81–85

    Article  PubMed  CAS  Google Scholar 

  11. Dai J, Weinberg RS, Waxman S, Jing Y (1999) Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 93:268–277

    PubMed  CAS  Google Scholar 

  12. Davison K, Cote S, Mader S, Miller WH (2003) Glutathione depletion overcomes resistance to arsenic trioxide in arsenic-resistant cell lines. Leukemia 17:931–940

    Article  PubMed  CAS  Google Scholar 

  13. Hayes JD, McLellan LI (1999) Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defense against oxidative stress. Free Radic Res 31:273–300

    Article  PubMed  CAS  Google Scholar 

  14. Pastore A, Federici G, Bertini E, Piemonte F (2003) Analysis of glutathione: implication in redox and detoxification. Clin Chim Acta 333:19–39

    Article  PubMed  CAS  Google Scholar 

  15. Davison K, Mann KK, Waxman S, Miller WH Jr (2004) JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocitic leukemia cells. Blood 103:3496–3502

    Article  PubMed  CAS  Google Scholar 

  16. Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD et al (1999) Regulation of JNK signaling by GSTp. EMBO J. 18:1321–1334

    Article  PubMed  CAS  Google Scholar 

  17. Bernardini S, Bellincampi L, Ballerini S, Ranalli M, Pastore A, Cortese C et al (2002) Role of GSTP1-1 in mediating the effect of etoposide on human neuroblastoma cell line SH-SY5Y. J Cell Biochem 86:340–347

    Article  PubMed  CAS  Google Scholar 

  18. Shen H, Tsuchida S, Tamai K, Sato K (1993) Identification of cysteine residues involved in disulfide formation in the inactivation of glutathione S-transferase P-form by hydrogen peroxide. Arch Biochem Biophys 300:137–141

    Article  PubMed  CAS  Google Scholar 

  19. Benedetti L, Grignani F, Scicchitano BM, Jetten AM, Diverio D, Lo Coco F et al (1996) Retinoic induced differentiation of acute promyelocitic leukemia involves PML-RARalpha mediated increase of type II transglutaminase. Blood 87:1939–1950

    PubMed  CAS  Google Scholar 

  20. Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S et al (2001) Hystone deacetylase target treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61:2–7

    PubMed  Google Scholar 

  21. Gianni M, Koken MHM, Chelbi-Alix MK, Benoit G, Lanotte M, Chen Z et al (1998) Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells. Blood 91:4300–4310

    PubMed  CAS  Google Scholar 

  22. Andersen AS, Junker S (1994) Simple and efficient recovery of rare living lymphoid cells from a vast majority of dead cells. Nucleic Acids Res 22:5769

    Article  PubMed  CAS  Google Scholar 

  23. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139:271–279

    Article  PubMed  CAS  Google Scholar 

  24. Bernardini S, Bernassola F, Cortese C, Ballerini S, Melino G, Motti C et al (2000) Modulation of GSTP1-1 activity by polymerization during apoptosis. J Cell Biochem 77:645–653

    Article  PubMed  CAS  Google Scholar 

  25. Jing Y, Dai J, Chalmers-Redman RME, Tatton WG, Waxman S (1999) Arsenic trioxide selectively induces acute promyelocitic leukemia cell apoptosis via hydrogen peroxide-dependent pathway. Neoplasia 94:2102–2111

    CAS  Google Scholar 

  26. Zhou L, Jing Y, Styblo M, Chen Z, Waxman S (2005) Glutathione-S-transferase π inhibits As2O3-induced apoptosis in lymphoma cells: involvement of hydrogen peroxide catabolism. Blood 105(3):1198–1203

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine and Department of Laboratory Medicine-Policlinico “Tor Vergata”, University of Rome “Tor Vergata”, Viale Oxford 81, 00133, Rome, Italy

    Sergio Bernardini, Marzia Nuccetelli, Lorenza Bellincampi & Giorgio Federici

  2. Proteomic group, Fondazione Santa Lucia-IRCCS, Rome, Italy

    Sergio Bernardini

  3. Department of Biopathology-PTV, University of Rome “Tor Vergata”, Rome, Italy

    Nélida I. Noguera & Francesco Lo Coco

  4. Department of Clinical Sciences, University of Parma, Parma, Italy

    Paolo Lunghi & Antonio Bonati

  5. Sir Mortimer B. Davis Jewish General Hospital, Institute for Medical Research, McGill University, Montreal, Canada

    Koren Mann & Wilson H. Miller Jr

  6. Laboratory of Clinical Chemistry, Bambino Gesù-IRCCS Hospital, Rome, Italy

    Giorgio Federici

Authors
  1. Sergio Bernardini
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  2. Marzia Nuccetelli
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  3. Nélida I. Noguera
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  4. Lorenza Bellincampi
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  5. Paolo Lunghi
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  6. Antonio Bonati
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  7. Koren Mann
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  8. Wilson H. Miller Jr
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  9. Giorgio Federici
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  10. Francesco Lo Coco
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Correspondence to Sergio Bernardini.

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Bernardini, S., Nuccetelli, M., Noguera, N.I. et al. Role of GSTP1-1 in mediating the effect of As2O3 in the Acute Promyelocytic Leukemia cell line NB4. Ann Hematol 85, 681–687 (2006). https://doi.org/10.1007/s00277-006-0139-8

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  • DOI: https://doi.org/10.1007/s00277-006-0139-8

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