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Acute Leukemias

A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

Leukemia volume 22, pages 1853–1863 (2008)Cite this article

A Corrigendum to this article was published on 11 February 2009

Abstract

Inorganic arsenic trioxide (As2O3) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As2O3 at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As2O3 resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As2O3. We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As2O3, although like As2O3, darinaparsin-induced toxicity is c-Jun NH2-terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor α (PML/RARα) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As2O3 treatment. This may be explained by our finding that As2O3, but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As2O3.

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References

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

    CAS  PubMed  Google Scholar 

  2. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006; 107: 2627–2632.

    Article  CAS  PubMed  Google Scholar 

  3. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol 2006; 17: 131–134.

    Article  CAS  PubMed  Google Scholar 

  4. Niu C, Yan H, Sun HP, Liu JX, Gu BW, Su XY et al. Treatment of de novo and relapsed acute promyelocytic patients with arsenic trioxide. Blood 1998; 92 (Suppl 1): 678a.

    Google Scholar 

  5. Miller Jr WH, Schipper HM, Lee JS, Singer J, Waxman S . Mechanisms of action of arsenic trioxide. Cancer Res 2002; 62: 3893–3903.

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Hughes MF . Arsenic toxicity and potential mechanisms of action. Toxicol Lett 2002; 133: 1–16.

    Article  CAS  PubMed  Google Scholar 

  8. Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W et al. 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 2003; 278: 37832–37839.

    Article  CAS  Google Scholar 

  9. Zheng Y, Yamaguchi H, Tian C, Lee MW, Tang H, Wang HG et al. Arsenic trioxide (As(2)O(3)) induces apoptosis through activation of Bax in hematopoietic cells. Oncogene 2005; 24: 3339–3347.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Lee TC, Wei ML, Chang WJ, Ho IC, Lo JF, Jan KY et al. Elevation of glutathione levels and glutathione S-transferase activity in arsenic-resistant Chinese hamster ovary cells. In Vitro Cell Dev Biol 1989; 25: 442–448.

    Article  CAS  PubMed  Google Scholar 

  12. Ochi T, Kaise T, Oya-Ohta Y . Glutathione plays different roles in the induction of the cytotoxic effects of inorganic and organic arsenic compounds in cultured BALB/c 3T3 cells. Experientia 1994; 50: 115–120.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Kajiguchi T, Yamamoto K, Iida S, Ueda R, Emi N, Naoe T . Sustained activation of c-jun-N-terminal kinase plays a critical role in arsenic trioxide-induced cell apoptosis in multiple myeloma cell lines. Cancer Sci 2006; 97: 540–545.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Akao Y, Mizoguchi H, Kojima S, Naoe T, Ohishi N, Yagi K . Arsenic induces apoptosis in B-cell leukaemic cell lines in vitro: activation of caspases and down-regulation of Bcl-2 protein. Br J Haematol 1998; 102: 1055–1060.

    Article  CAS  PubMed  Google Scholar 

  17. Uslu R, Sanli UA, Sezgin C, Karabulut B, Terzioglu E, Omay SB et al. Arsenic trioxide-mediated cytotoxicity and apoptosis in prostate and ovarian carcinoma cell lines. Clin Cancer Res 2000; 6: 4957–4964.

    CAS  PubMed  Google Scholar 

  18. Hyun Park W, Hee Cho Y, Won Jung C, Oh Park J, Kim K, Hyuck Im Y et al. Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis. Biochem Biophys Res Commun 2003; 300: 230–235.

    Article  PubMed  Google Scholar 

  19. Chen GQ, Zhou L, Styblo M, Walton F, Jing Y, Weinberg R et al. Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. Cancer Res 2003; 63: 1853–1859.

    CAS  PubMed  Google Scholar 

  20. Waxman S, Anderson KC . History of the development of arsenic derivatives in cancer therapy. Oncologist 2001; 6 (Suppl 2): 3–10.

    Article  CAS  PubMed  Google Scholar 

  21. Camacho LH, Hong D, Gutierrez C, Vertovsek S, Tannir N, Parker CA, Purdom MA et al. Phase-1 trial of ZIO-101, a novel organic arsenic in patients with advanced cancers (abstract). J Clin Oncol 2006; 24 (18S): p 605S.

  22. Roussel MJ, Lanotte M . Maturation sensitive and resistant t(15;17) NB4 cell lines as tools for APL physiopathology: nomenclature of cells and repertory of their known genetic alterations and phenotypes. Oncogene 2001; 20: 7287–7291.

    Article  CAS  PubMed  Google Scholar 

  23. Hardin JA, Sherr DH, DeMaria M, Lopez PA . A simple fluorescence method for surface antigen phenotyping of lymphocytes undergoing DNA fragmentation. J Immunol Methods 1992; 154: 99–107.

    Article  CAS  PubMed  Google Scholar 

  24. Stuurman N, de Graaf A, Floore A, Josso A, Humbel B, de Jong L et al. A monoclonal antibody recognizing nuclear matrix-associated nuclear bodies. J Cell Sci 1992; 101 (Part 4): 773–784.

    Google Scholar 

  25. Diaz Z, Colombo M, Mann KK, Su H, Smith KN, Bohle DS et al. Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines. Blood 2005; 105: 1237–1245.

    Article  CAS  PubMed  Google Scholar 

  26. Shao W, Fanelli M, Ferrara FF, Riccioni R, Rosenauer A, Davison K et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells. J Natl Cancer Inst 1998; 90: 124–133.

    Article  CAS  PubMed  Google Scholar 

  27. Stadtman ER . Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. Free Radic Biol Med 1990; 9: 315–325.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Besselink GA, van Engelenburg FA, Ebbing IG, Hilarius PM, de Korte D, Verhoeven AJ . Additive effects of dipyridamole and trolox in protecting human red cells during photodynamic treatment. Vox Sang 2003; 85: 25–30.

    Article  CAS  PubMed  Google Scholar 

  30. Aruoma OI, Halliwell B, Hoey BM, Butler J . The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 1989; 6: 593–597.

    Article  CAS  PubMed  Google Scholar 

  31. Maeda H, Hori S, Ohizumi H, Segawa T, Kakehi Y, Ogawa O et al. Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine. Cell Death Differ 2004; 11: 737–746.

    Article  CAS  PubMed  Google Scholar 

  32. Bailey HH . L-S,R-Buthionine sulfoximine: historical development and clinical issues. Chem Biol Interact 1998; 111–112: 239–254.

    Article  PubMed  Google Scholar 

  33. Cross JV, Deak JC, Rich EA, Qian Y, Lewis M, Parrott LA et al. Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. J Biol Chem 1999; 274: 31150–31154.

    Article  CAS  PubMed  Google Scholar 

  34. Vernhet L, Allain N, Payen L, Anger JP, Guillouzo A, Fardel O . Resistance of human multidrug resistance-associated protein 1-overexpressing lung tumor cells to the anticancer drug arsenic trioxide. Biochem Pharmacol 2001; 61: 1387–1391.

    Article  CAS  PubMed  Google Scholar 

  35. Wang ZG, Rivi R, Delva L, Konig A, Scheinberg DA, Gambacorti-Passerini C et al. Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in a PML and PML-RARalpha independent manner. Blood 1998; 92: 1497–1504.

    CAS  PubMed  Google Scholar 

  36. Chou WC, Jie C, Kenedy AA, Jones RJ, Trush MA, Dang CV . Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci USA 2004; 101: 4578–4583.

    Article  CAS  PubMed  Google Scholar 

  37. Woo SH, Park IC, Park MJ, Lee HC, Lee SJ, Chun YJ et al. Arsenic trioxide induces apoptosis through a reactive oxygen species-dependent pathway and loss of mitochondrial membrane potential in HeLa cells. Int J Oncol 2002; 21: 57–63.

    CAS  PubMed  Google Scholar 

  38. Sakurai T, Kojima C, Kobayashi Y, Hirano S, Sakurai MH, Waalkes MP et al. Toxicity of a trivalent organic arsenic compound, dimethylarsinous glutathione in a rat liver cell line (TRL 1215). Br J Pharmacol 2006; 149: 888–897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hirano S, Kobayashi Y, Cui X, Kanno S, Hayakawa T, Shraim A . The accumulation and toxicity of methylated arsenicals in endothelial cells: important roles of thiol compounds. Toxicol Appl Pharmacol 2004; 198: 458–467.

    Article  CAS  PubMed  Google Scholar 

  40. Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, Zimmermann U et al. Forced uptake of trivalent and pentavalent methylated and inorganic arsenic and its cyto-/genotoxicity in fibroblasts and hepatoma cells. Toxicol Sci 2005; 87: 46–56.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Mrs Glenna Keating and Isabelle Richer for help with the atomic absorption, Dr Haixiang Su for help with the protein carbonyl experiments, and Dr Ivan Toposirivic for confocal microscopy expertise. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and the Samuel Waxman Foundation (to WH Miller Jr). WM is a Chercheur National of Fonds de la Recherche en Santé du Quebec (FRSQ). SM is supported by fellowship from the Montreal Centre for Experimental Therapeutics in Cancer. ZD is supported by a Canadian Graduate Scholarship from the CIHR. Ziopharm Oncology Inc., has provided financial support for the experiments reported in this paper.

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Author notes

  1. Z Diaz, K K Mann and S Marcoux: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Segal Cancer Comprehensive Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Quebec, Canada

    Z Diaz, K K Mann, S Marcoux, M Kourelis, M Colombo & W H Miller Jr

  2. ZioPharm Oncology, Inc., Boston, Massachusetts, USA

    P B Komarnitsky

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  1. Z Diaz
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Correspondence to W H Miller Jr.

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Diaz, Z., Mann, K., Marcoux, S. et al. A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. Leukemia 22, 1853–1863 (2008). https://doi.org/10.1038/leu.2008.194

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