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Antimony-trioxide- and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system

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Abstract

During the last years remission rates of more than 72% for arsenic(III)-oxide (As2O3) treatment in relapsed or refractory acute promyelocytic leukemia have been published. As2O3 is under clinical investigation for therapy of leukemia and solid tumors. Due to the chemical affinity of arsenic and antimony, we analyzed the potency of antimony(III)-oxide (Sb2O3) to exert As2O3-like effects. Based on the same molar concentrations, lower efficacy in apoptosis induction and caspase-independent decrease of mitochondrial membrane potential was observed for Sb2O3. No difference in sensitivity to As2O3 or Sb2O3 was detected in CEM cells when compared to their multiple drug resistant derivatives. Apoptosis was induced by combining sub-apoptotic concentrations of Sb2O3 or As2O3 with sub-apoptotic concentrations of dl-buthionine-[S,R]-sulfoximine (BSO). Other modulators of the cellular redox system showed this effect to a lower extent and enhancement was not consistent for the different cell lines tested. Caspase inhibitors protected cell lines from Sb2O3- and As2O3-induced apoptosis. When BSO was added, the inhibitors lost their protective ability. The ability of modulators of the cellular redox system in clinically applicable concentrations to enhance the apoptotic effects of the two oxides in a synergistic way may be helpful to reduce their toxicity by optimizing their dose.

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References

  1. Rojewski MT, Korper S, Schrezenmeier H (2004) Arsenic trioxide therapy in acute promyelocytic leukemia and beyond: from bench to bedside. Leuk Lymphoma 45:2387–2401. doi:10.1080/10428190412331272686

    Article  PubMed  CAS  Google Scholar 

  2. Amadori S, Fenaux P, Ludwig H, O’Dwyer M, Sanz M (2005) Use of arsenic trioxide in haematological malignancies: insight into the clinical development of a novel agent. Curr Med Res Opin 21:403–411. doi:10.1185/030079904X20349

    Article  PubMed  CAS  Google Scholar 

  3. Bonati A, Rizzoli V, Lunghi P (2006) Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug. Curr Pharm Biotechnol 7:397–405. doi:10.2174/138920106779116829

    Article  PubMed  CAS  Google Scholar 

  4. Douer D, Tallman MS (2005) Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol 23:2396–2410. doi:10.1200/JCO.2005.10.217

    Article  PubMed  CAS  Google Scholar 

  5. Kalmadi SR, Hussein MA (2006) The emerging role of arsenic trioxide as an immunomodulatory agent in the management of multiple myeloma. Acta Haematol 116:1–7. doi:10.1159/000092341

    Article  PubMed  CAS  Google Scholar 

  6. Muller S, Matunis MJ, Dejean A (1998) Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 17:61–70. doi:10.1093/emboj/17.1.61

    Article  PubMed  CAS  Google Scholar 

  7. Muller S, Miller WH Jr, Dejean A (1998) Trivalent antimonials induce degradation of the PML-RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB4 cells. Blood 92:4308–4316

    PubMed  CAS  Google Scholar 

  8. Sternsdorf T, Puccetti E, Jensen K et al (1999) PIC-1/SUMO-1-modified PML-retinoic acid receptor alpha mediates arsenic trioxide-induced apoptosis in acute promyelocytic leukemia. Mol Cell Biol 19:5170–5178

    PubMed  CAS  Google Scholar 

  9. Lallemand-Breitenbach V, Zhu J, Puvion F et al (2001) Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11 S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 193:1361–1371. doi:10.1084/jem.193.12.1361

    Article  PubMed  CAS  Google Scholar 

  10. Chen GQ, Shi XG, Tang W et al (1997) Use of arsenic trioxide (As2O3) 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 

  11. Bruserud O, Gjertsen BT, Huang T (2000) Induction of differentiation and apoptosis—a possible strategy in the treatment of adult acute myelogenous leukemia. Oncologist 5:454–462. doi:10.1634/theoncologist.5-6-454

    Article  PubMed  CAS  Google Scholar 

  12. Calleja EM, Warrell RP (2000) Differentiating agents in pediatric malignancies: all-trans-retinoic acid and arsenic in acute promyelocytic leukemia. Curr Oncol Rep 2:519–523. doi:10.1007/s11912-000-0105-x

    Article  PubMed  CAS  Google Scholar 

  13. Huff J, Waalkes M, Nyska A, Chan P (1999) Re: apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 91:1690–1691. doi:10.1093/jnci/91.19.1690 letter

    Article  PubMed  CAS  Google Scholar 

  14. Zhu XH, Shen YL, Jing YK et al (1999) Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 91:772–778. doi:10.1093/jnci/91.9.772

    Article  PubMed  CAS  Google Scholar 

  15. Rojewski MT, Körper S, Thiel E, Schrezenmeier H (2004) Depolarization of mitochondria and activation of caspases are common features of arsenic(III)-induced apoptosis in myelogenic and lymphatic cell lines. Chem Res Toxicol 17:119–128. doi:10.1021/tx034104+

    Article  PubMed  CAS  Google Scholar 

  16. Nolte F, Friedrich O, Rojewski M, Fink RH, Schrezenmeier H, Korper S (2004) Depolarisation of the plasma membrane in the arsenic trioxide (As2O3)-and anti-CD95-induced apoptosis in myeloid cells. FEBS Lett 578:85–89. doi:10.1016/j.febslet.2004.10.075

    Article  PubMed  CAS  Google Scholar 

  17. Korper S, Nolte F, Thiel E, Schrezenmeier H, Rojewski MT (2004) The role of mitochondrial targeting in arsenic trioxide-induced apoptosis in myeloid cell lines. Br J Haematol 124:186–189. doi:10.1046/j.1365-2141.2003.04742.x

    Article  PubMed  Google Scholar 

  18. Tsai S, Hsieh M, Chen L, Liang Y, Lin J, Lin S (2001) Suppression of Fas ligand expression on endothelial cells by arsenite through reactive oxygen species. Toxicol Lett 123:11–19. doi:10.1016/S0378-4274(01) 00373-3

    Article  PubMed  CAS  Google Scholar 

  19. Yi J, Gao F, Shi G, Li H, Shi X, Tang X (2002) Apoptosis susceptibility of tumor cells to arsenic trioxide and the inherent cellular level of reactive oxygen species. Chin Med J (Engl) 115:603–606

    CAS  Google Scholar 

  20. Nakagawa Y, Akao Y, Morikawa H et al (2002) Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines. Life Sci 70:2253–2269. doi:10.1016/S0024-3205(01) 01545-4

    Article  PubMed  CAS  Google Scholar 

  21. Choi YJ, Park JW, Suh SI et al (2002) Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt. Int J Oncol 21:603–610

    PubMed  CAS  Google Scholar 

  22. Rojewski MT, Baldus C, Knauf W, Thiel E, Schrezenmeier H (2002) Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation. Br J Haematol 116:555–563. doi:10.1046/j.0007-1048.2001.03298.x

    Article  PubMed  CAS  Google Scholar 

  23. Martensson J, Meister A (1991) Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. Proc Natl Acad Sci USA 88:4656–4660. doi:10.1073/pnas.88.11.4656

    Article  PubMed  CAS  Google Scholar 

  24. Wu D, Cederbaum A (2004) Glutathione depletion in CYP2E1-expressing liver cells induces toxicity due to the activation of p38 mitogen-activated protein kinase and reduction of nuclear factor-kappaB DNA binding activity. Mol Pharmacol 66:749–760. doi:10.1124/mol.104.002048

    Article  PubMed  CAS  Google Scholar 

  25. Macho A, Decaudin D, Castedo M et al (1996) Chloromethyl-X-Rosamine is an aldehyde-fixable potential-sensitive fluorochrome for the detection of early apoptosis. Cytometry 25:333–340. doi:10.1002/(SICI) 1097-0320(19961201) 25:4<333::AID-CYTO4>3.0.CO;2-E

    Article  PubMed  CAS  Google Scholar 

  26. Gilmore K, Wilson M (1999) The use of chloromethyl-X-rosamine (Mitotracker red) to measure loss of mitochondrial membrane potential in apoptotic cells is incompatible with cell fixation. Cytometry 36:355–358. doi:10.1002/(SICI) 1097-0320(19990801) 36:4<355::AID-CYTO11>3.0.CO;2-9

    Article  PubMed  CAS  Google Scholar 

  27. Leira F, Vieites JM, Vieytes MR, Botana LM (2001) Apoptotic events induced by the phosphatase inhibitor okadaic acid in normal human lung fibroblasts. Toxicol In Vitro 15:199–208. doi:10.1016/S0887-2333(01) 00013-3

    Article  PubMed  CAS  Google Scholar 

  28. Buckman JF, Hernandez H, Kress GJ, Votyakova TV, Pal S, Reynolds IJ (2001) MitoTracker labeling in primary neuronal and astrocytic cultures: influence of mitochondrial membrane potential and oxidants. J Neurosci Methods 104:165–176. doi:10.1016/S0165-0270(00) 00340-X

    Article  PubMed  CAS  Google Scholar 

  29. Soignet SL, Maslak P, Wang ZG et al (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339:1341–1348. doi:10.1056/NEJM199811053391901

    Article  PubMed  CAS  Google Scholar 

  30. Shen ZX, Chen GQ, Ni JH et al (1997) Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360

    PubMed  CAS  Google Scholar 

  31. Kapoor R, Slade DL, Fujimori A, Pommier Y, Harker WG (1995) Altered topoisomerase I expression in two subclones of human CEM leukemia selected for resistance to camptothecin. Oncol Res 7:83–95

    PubMed  CAS  Google Scholar 

  32. Fujimori A, Harker WG, Kohlhagen G, Hoki Y, Pommier Y (1995) Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin. Cancer Res 55:1339–1346

    PubMed  CAS  Google Scholar 

  33. Zhang P, Wang SY, Hu XH (1996) Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 17:58–62

    Google Scholar 

  34. Mathews V, Balasubramanian P, Shaji RV, George B, Chandy M, Srivastava A (2002) Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience. Am J Hematol 70:292–299. doi:10.1002/ajh.10138

    Article  PubMed  CAS  Google Scholar 

  35. Niu C, Yan H, Yu T et al (1999) Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94:3315–3324

    PubMed  CAS  Google Scholar 

  36. Spencer A, Firkin F (1999) Arsenic trioxide treatment of relapsed acute promyelocytic leukaemia: initial Australian experience. Aust N Z J Med 29:385–386 letter

    PubMed  CAS  Google Scholar 

  37. Warrell RP Jr, Soignet SL, Maslak P et al (1998) Initial Western study of arsenic trioxide in acute promyelocytic leukemia. J Clin Oncol 17(Suppl.):19

    Google Scholar 

  38. Ohnishi K, Yoshida H, Shigeno K et al (2002) Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia 16:617–622. doi:10.1038/sj.leu.2402426

    Article  PubMed  CAS  Google Scholar 

  39. Hu J, Shen ZX, Sun GL, Chen SJ, Wang ZY, Chen Z (1999) Long-term survival and prognostic study in acute promyelocytic leukemia treated with all-trans-retinoic acid, chemotherapy, and As2O3: an experience of 120 patients at a single institution. Int J Hematol 70:248–260

    PubMed  CAS  Google Scholar 

  40. Hu J, Shen Z, Sun H et al (2000) Long-term survey of outcome in acute promyelocytic leukemia. Chin Med J (Engl) 113:107–110. doi:10.3901/JME.2000.08.107

    Article  CAS  Google Scholar 

  41. Soignet SL, Frankel SR, Douer D 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 

  42. Ni J, Chen G, Shen Z et al (1998) Pharmacokinetics of intravenous arsenic trioxide in the treatment of acute promyelocytic leukemia. Chin Med J (Engl) 111:1107–1110

    CAS  Google Scholar 

  43. Soignet SL (2001) Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia. Oncologist 6:11–16. doi:10.1634/theoncologist.6-suppl_2-11

    Article  PubMed  CAS  Google Scholar 

  44. Jiong H, Zhixiang S, Wen W, Xiusong L, Guanlin S, Zhenyi W (2000) Long-term survey of outcome in acute promyelocytic leukemia. Chin Med J (Engl) 113:107–110

    Google Scholar 

  45. Camacho LH, Soignet SL, Chanel S et al (2000) Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol 18:2620–2625

    PubMed  CAS  Google Scholar 

  46. Hussein MA, Elson P, Reed J et al (2003) Arsenic trioxide (Trisenox™), ascorbic acid (AA), and dexamethasone (Dex) pulses-TAD for relapsed refractory progressive multiple myeloma patients. Hematol J 4:S257

    Google Scholar 

  47. Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I et al (2002) Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res 8:3658–3668

    PubMed  CAS  Google Scholar 

  48. Munshi NC, Desikan R, Zangari M (1999) Marked anti-tumor effect of arsenic trioxide (As2O3) in high risk refractory multiple myeloma. Blood 94:123a

    Google Scholar 

  49. Munshi NC, Hideshima T, Chauhan D, Richardson P, Anderson KC (2002) Novel biologically based therapies for multiple myeloma. Int J Hematol 76:340–341

    Article  PubMed  Google Scholar 

  50. Munshi NC, Tricot G, Desikan R et al (2002) Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 16:1835–1837. doi:10.1038/sj.leu.2402599

    Article  PubMed  CAS  Google Scholar 

  51. Donelli A, Chiodino C, Panissidi T, Roncaglia R, Torelli G (2000) Might arsenic trioxide be useful in the treatment of advanced myelodysplastic syndromes? Haematologica 85:1002–1003

    PubMed  CAS  Google Scholar 

  52. Cheson BD, Zwiebel JA, Dancey J, Murgo A (2000) Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 27:560–577

    PubMed  CAS  Google Scholar 

  53. List A, Beran M, DiPersio J et al (2003) Opportunities for Trisenox (arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia 17:1499–1507. doi:10.1038/sj.leu.2403021

    Article  PubMed  CAS  Google Scholar 

  54. Vuky J, Yu R, Schwartz L, Motzer RJ (2002) Phase II trial of arsenic trioxide in patients with metastatic renal cell carcinoma. Invest New Drugs 20:327–330. doi:10.1023/A:1016270206374

    Article  PubMed  CAS  Google Scholar 

  55. Lecureur V, Lagadic-Gossmann D, Fardel O (2002) Potassium antimonyl tartrate induces reactive oxygen species-related apoptosis in human myeloid leukemic HL60 cells. Int J Oncol 20:1071–1076

    PubMed  CAS  Google Scholar 

  56. Mann KK, Davison K, Colombo M et al (2006) Antimony trioxide-induced apoptosis is dependent on SEK1/JNK signaling. Toxicol Lett 160:158–170. doi:10.1016/j.toxlet.2005.06.017

    Article  PubMed  CAS  Google Scholar 

  57. Gartenhaus RB, Prachand SN, Paniaqua M, Li Y, Gordon LI (2002) Arsenic trioxide cytotoxicity in steroid and chemotherapy-resistant myeloma cell lines: enhancement of apoptosis by manipulation of cellular redox state. Clin Cancer Res 8:566–572

    PubMed  CAS  Google Scholar 

  58. Chouchane S, Snow ET (2001) In vitro effect of arsenical compounds on glutathione-related enzymes. Chem Res Toxicol 14:517–522. doi:10.1021/tx000123x

    Article  PubMed  CAS  Google Scholar 

  59. Larochette N, Decaudin D, Jacotot E et al (1999) Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp Cell Res 249:413–421. doi:10.1006/excr.1999.4519

    Article  PubMed  CAS  Google Scholar 

  60. Griffith OW (1982) Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem 257:13704–13712

    PubMed  CAS  Google Scholar 

  61. 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 

  62. Jing Y, Dai J, Chalmers-Redman RM, Tatton WG, Waxman S (1999) Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 94:2102–2111

    PubMed  CAS  Google Scholar 

  63. Chattopadhyay S, Ghosh S, Debnath J, Ghosh D (2001) Protection of sodium arsenite-induced ovarian toxicity by coadministration of l-ascorbate (vitamin C) in mature Wistar strain rat. Arch Environ Contam Toxicol 41:83–89. doi:10.1007/s002440010223

    Article  PubMed  CAS  Google Scholar 

  64. Block G, Henson DE, Levine M (1991) Vitamin C: a new look. Ann Intern Med 114:909–910

    PubMed  CAS  Google Scholar 

  65. Bijur GN, Ariza ME, Hitchcock CL, Williams MV (1997) Antimutagenic and promutagenic activity of ascorbic acid during oxidative stress. Environ Mol Mutagen 30:339–345. doi:10.1002/(SICI) 1098-2280(1997) 30:3<339::AID-EM13>3.0.CO;2-E

    Article  PubMed  CAS  Google Scholar 

  66. Sakagami H, Satoh K (1997) Modulating factors of radical intensity and cytotoxic activity of ascorbate. Anticancer Res 17:3513–3520 Review

    PubMed  CAS  Google Scholar 

  67. Subbarayan PR, Lima M, Ardalan B (2007) Arsenic trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol 46:557–561. doi:10.1080/02841860601042456

    Article  PubMed  CAS  Google Scholar 

  68. Berenson JR, Matous J, Swift RA, Mapes R, Morrison B, Yeh HS (2007) A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 13:1762–1768. doi:10.1158/1078-0432.CCR-06-1812

    Article  PubMed  CAS  Google Scholar 

  69. Wu KL, Beksac M, van Droogenbroeck J, Amadori S, Zweegman S, Sonneveld P (2006) Phase II multicenter study of arsenic trioxide, ascorbic acid and dexamethasone in patients with relapsed or refractory multiple myeloma. Haematologica 91:1722–1723

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Medizinische Klinik III (Hämatologie, Onkologie und Transfusionsmedizin), Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany

    Susan Lösler, Sarah Schlief, Christiane Kneifel & Eckhard Thiel

  2. Augenklinik, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany

    Christiane Kneifel

  3. Institut für Transfusionsmedizin, Universität Ulm, Helmholtzstraße 10, 89081, Ulm, Germany

    Hubert Schrezenmeier & Markus T. Rojewski

  4. Institut für klinische Transfusionsmedizin und Immungenetik, DRK Blutspendedienst Baden-Württemberg—Hessen, Helmholtzstraße 10, 89081, Ulm, Germany

    Hubert Schrezenmeier & Markus T. Rojewski

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  1. Susan Lösler
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Lösler, S., Schlief, S., Kneifel, C. et al. Antimony-trioxide- and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system. Ann Hematol 88, 1047–1058 (2009). https://doi.org/10.1007/s00277-009-0736-4

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