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Selenium pp 251-269 | Cite as

Therapeutic Potential of Selenium Compounds in the Treatment of Cancer

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Part of the Molecular and Integrative Toxicology book series (MOLECUL)

Abstract

The potential applications of different selenium compounds as cancer chemotherapeutic agents is an active area of research within the field of cancer drug discovery. The antineoplastic efficacies of many of these small molecules have been extensively investigated, mainly in multiple preclinical models of cancer. Sodium selenite and Se-methylselenocysteine represent two of such selenium compounds, the cytotoxic and antiproliferative efficacies of which are discussed herein. These compounds differ in their mechanisms of action. Sodium selenite exerts its cytotoxic effects by directly oxidizing cellular free thiol pools. In contrast, Se-methylselenocysteine undergoes enzymatic transformation into methylselenol which is cytotoxic due to its ability to redox cycle with cellular thiols. Despite the inherent differences in their metabolic transformations, the disruption of the cellular redox balance and the activation of pro-death intracellular signaling pathways have been implicated as the most prevalent mechanisms of their cytotoxic effects. Both of these selenium compounds exert synergistic toxic effects with certain cancer chemotherapeutics. Together, the well-documented tumor-specific cytotoxic and antiproliferative effects of these compounds have paved the path for their clinical translation. In a phase I clinical trial, it has been shown that sodium selenite is well tolerated in human up to a dose of 10.2 mg/m2 when administered daily for 5 days a week for 2 weeks. Similarly, Se-methylselenocysteine exhibits a favorable pharmacokinetic and safety profile during prolonged oral administration in healthy subjects. Further studies are warranted to investigate their cancer chemotherapeutic efficacies in clinical settings.

Keywords

Cancer Sodium selenite Se-methylselenocysteine Selenium metabolism Phase I clinical trial Chemotherapeutic agents 

Notes

Acknowledgments

The authors would like to thank financial support from Barncancerfonden, Cancerfonden, Cancer- och Allergifonden, KI Fonder, Jochnick Foundation, Radiumhemmetsforsknings fonder, and the County Council of Stockholm.

References

  1. Akladios FN, et al. Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I. Bioorg Med Chem Lett. 2012;22(4):1579–81.PubMedCrossRefGoogle Scholar
  2. Andreadou I, et al. Synthesis of novel Se-substituted selenocysteine derivatives as potential kidney selective prodrugs of biologically active selenol compounds: evaluation of kinetics of beta-elimination reactions in rat renal cytosol. J Med Chem. 1996;39(10):2040–6.PubMedCrossRefGoogle Scholar
  3. Baldew GS, et al. Selenium-induced protection against cis-diamminedichloroplatinum(II) nephrotoxicity in mice and rats. Cancer Res. 1989;49(11):3020–3.PubMedGoogle Scholar
  4. Bannai S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem. 1986;261(5):2256–63.Google Scholar
  5. Bhattacharya A. Methylselenocysteine: a promising antiangiogenic agent for overcoming drug delivery barriers in solid malignancies for therapeutic synergy with anticancer drugs. Expert Opin Drug Deliv. 2011;8(6):749–63.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bjorkhem-Bergman L, et al. Drug-resistant human lung cancer cells are more sensitive to selenium cytotoxicity. Effects on thioredoxin reductase and glutathione reductase. Biochem Pharmacol. 2002;63(10):1875–84.PubMedCrossRefGoogle Scholar
  7. Bjorkhem-Bergman L, et al. Selenium prevents tumor development in a rat model for chemical carcinogenesis. Carcinogenesis. 2005;26(1):125–31.PubMedCrossRefGoogle Scholar
  8. Bjornstedt M, Kumar S, Holmgren A. Selenodiglutathione is a highly efficient oxidant of reduced thioredoxin and a substrate for mammalian thioredoxin reductase. J Biol Chem. 1992;267(12):8030–4.PubMedGoogle Scholar
  9. Bjornstedt M, Kumar S, Holmgren A. Selenite and selenodiglutathione: reactions with thioredoxin systems. Methods Enzymol. 1995;252:209–19.PubMedCrossRefGoogle Scholar
  10. Brinkman M, et al. Use of selenium in chemoprevention of bladder cancer. Lancet Oncol. 2006;7(9):766–74.PubMedCrossRefGoogle Scholar
  11. Brodin O, et al. Pharmacokinetics and toxicity of sodium selenite in the treatment of patients with carcinoma in a phase I clinical trial: the SECAR study. Nutrients. 2015;7(6):4978–94.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Caffrey PB, Frenkel GD. Selenite cytotoxicity in drug resistant and nonresistant human ovarian tumor cells. Cancer Res. 1992;52(17):4812–6.PubMedGoogle Scholar
  13. Cao S, Durrani FA, Rustum YM. Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin Cancer Res. 2004;10(7):2561–9.PubMedCrossRefGoogle Scholar
  14. Cao S, et al. Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models. Br J Cancer. 2014;110(7):1733–43.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chen T, Wong YS. Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation. J Agric Food Chem. 2008;56(22):10574–81.PubMedCrossRefGoogle Scholar
  16. Chintala S, et al. Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1alpha. Cancer Chemother Pharmacol. 2010;66(5):899–911.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Clark LC, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276(24):1957–63.PubMedCrossRefGoogle Scholar
  18. Commandeur JN, et al. Bioactivation of selenocysteine Se-conjugates by a highly purified rat renal cysteine conjugate beta-lyase/glutamine transaminase K. J Pharmacol Exp Ther. 2000;294(2):753–61.PubMedGoogle Scholar
  19. Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): cystine supplier and beyond. Amino Acids. 2012;42(1):231–46.PubMedCrossRefGoogle Scholar
  20. Cooper AJ, Pinto JT. Aminotransferase, L-amino acid oxidase and beta-lyase reactions involving L-cysteine S-conjugates found in allium extracts. Relevance to biological activity? Biochem Pharmacol. 2005;69(2):209–20.PubMedCrossRefGoogle Scholar
  21. Cooper AJL, et al. Substrate specificity of human glutamine transaminase K as an aminotransferase and as a cysteine S-conjugate beta-lyase. Arch Biochem Biophys. 2008;474(1):72–81.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cooper AJ, et al. Cysteine S-conjugate beta-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents. Amino Acids. 2011;41(1):7–27.PubMedCrossRefGoogle Scholar
  23. Coyne CP, Jones T, Bear R. Simultaneous dual selective targeted delivery of two covalent gemcitabine immunochemotherapeutics and complementary anti-neoplastic potency of [Se]-methylselenocysteine. J Cancer Ther. 2015;6(1):62–89.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Eliot AC, Kirsch JF. Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations. Annu Rev Biochem. 2004;73:383–415.CrossRefGoogle Scholar
  25. Fernandes AP, et al. Methylselenol formed by spontaneous methylation of selenide is a superior selenium substrate to the thioredoxin and glutaredoxin systems. PLoS One. 2012;7(11):e50727.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Finley JW. Bioavailability of selenium from foods. Nutr Rev. 2006;64(3):146–51.PubMedCrossRefGoogle Scholar
  27. Gabel-Jensen C, Lunoe K, Gammelgaard B. Formation of methylselenol, dimethylselenide and dimethyldiselenide in in vitro metabolism models determined by headspace GC-MS. Metallomics. 2010;2(2):167–73.PubMedCrossRefGoogle Scholar
  28. Ganyc D, Self WT. High affinity selenium uptake in a keratinocyte model. FEBS Lett. 2008;582(2):299–304.PubMedCrossRefGoogle Scholar
  29. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–47.PubMedCrossRefGoogle Scholar
  30. Han Q, et al. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci. 2010;67(3):353–68.PubMedCrossRefGoogle Scholar
  31. Huang G, et al. Analysis of selenium levels in osteosarcoma patients and the effects of Se-methylselenocysteine on osteosarcoma cells in vitro. Nutr Cancer. 2015;67(5):847–56.PubMedCrossRefGoogle Scholar
  32. Husbeck B, Peehl DM, Knox SJ. Redox modulation of human prostate carcinoma cells by selenite increases radiation-induced cell killing. Free Radic Biol Med. 2005;38(1):50–7.PubMedCrossRefGoogle Scholar
  33. Husbeck B, et al. Tumor-selective killing by selenite in patient-matched pairs of normal and malignant prostate cells. Prostate. 2006;66(2):218–25.PubMedCrossRefGoogle Scholar
  34. Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer. 2003;3(4):276–85.PubMedCrossRefGoogle Scholar
  35. Hussain SP, et al. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res. 2004;64(7):2350–6.PubMedCrossRefGoogle Scholar
  36. Ip C, et al. Chemical form of selenium, critical metabolites, and cancer prevention. Cancer Res. 1991;51(2):595–600.PubMedGoogle Scholar
  37. Jackson MI, Combs GF Jr. Selenium and anticarcinogenesis: underlying mechanisms. Curr Opin Clin Nutr Metab Care. 2008;11(6):718–26.PubMedCrossRefGoogle Scholar
  38. Jia X, Li N, Chen J. A subchronic toxicity study of elemental Nano-Se in Sprague-Dawley rats. Life Sci. 2005;76(17):1989–2003.PubMedCrossRefGoogle Scholar
  39. Jiang C, et al. Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake. Mol Carcinog. 1999;26(4):213–25.PubMedCrossRefGoogle Scholar
  40. Johnson WD, et al. Subchronic oral toxicity studies of Se-methylselenocysteine, an organoselenium compound for breast cancer prevention. Food Chem Toxicol. 2008;46(3):1068–78.PubMedCrossRefGoogle Scholar
  41. Jonsson-Videsater K, et al. Selenite-induced apoptosis in doxorubicin-resistant cells and effects on the thioredoxin system. Biochem Pharmacol. 2004;67(3):513–22.PubMedCrossRefGoogle Scholar
  42. Jorgenson TC, Zhong W, Oberley TD. Redox imbalance and biochemical changes in cancer. Cancer Res. 2013;73(20):6118–23.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kellen E, Zeegers M, Buntinx F. Selenium is inversely associated with bladder cancer risk: a report from the Belgian case-control study on bladder cancer. Int J Urol. 2006;13(9):1180–4.PubMedCrossRefGoogle Scholar
  44. Kim EH, et al. Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res. 2007;67(13):6314–24.PubMedCrossRefGoogle Scholar
  45. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239–67.PubMedCrossRefGoogle Scholar
  46. Kumar S, Bjornstedt M, Holmgren A. Selenite is a substrate for calf thymus thioredoxin reductase and thioredoxin and elicits a large non-stoichiometric oxidation of NADPH in the presence of oxygen. Eur J Biochem. 1992;207(2):435–9.PubMedCrossRefGoogle Scholar
  47. Lee JI, et al. Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells. Cancer Prev Res (Phila). 2009a;2(7):683–93.CrossRefGoogle Scholar
  48. Lee JT, et al. Se-methylselenocysteine sensitized TRAIL-mediated apoptosis via down-regulation of Bcl-2 expression. Int J Oncol. 2009b;34(5):1455–60.PubMedGoogle Scholar
  49. Mangiapane E, Pessione A, Pessione E. Selenium and selenoproteins: an overview on different biological systems. Curr Protein Pept Sci. 2014;15(6):598–607.PubMedCrossRefGoogle Scholar
  50. Marshall JR, et al. Selenomethionine and methyl selenocysteine: multiple-dose pharmacokinetics in selenium-replete men. Oncotarget. 2017;8(16):26312–22.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Menter DG, Sabichi AL, Lippman SM. Selenium effects on prostate cell growth. Cancer Epidemiol Biomark Prev. 2000;9(11):1171–82.Google Scholar
  52. Misra S, Kwong RWM, Niyogi S. Transport of selenium across the plasma membrane of primary hepatocytes and enterocytes of rainbow trout. J Exp Biol. 2012;215(9):1491–501.PubMedCrossRefGoogle Scholar
  53. Misra S, et al. Redox-active selenium compounds-from toxicity and cell death to cancer treatment. Nutrients. 2015a;7(5):3536–56.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Misra S, Wallenberg M, Brodin O, Bjornstedt M. Selenite in cancer therapy. In: Brigelius-Flohe R, Sies H, editors. Diversity of selenium functions in health and disease, vol. 38. Boca Raton: CRC Press; 2015b. p. 400.Google Scholar
  55. Misra S, et al. Selenite promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells. Oncotarget. 2016;7(46):74686–700.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Mistry AR, et al. The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev. 2003;17(2):71–97.PubMedCrossRefGoogle Scholar
  57. Nian H, et al. Alpha-keto acid metabolites of organoselenium compounds inhibit histone deacetylase activity in human colon cancer cells. Carcinogenesis. 2009;30(8):1416–23.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Nilsonne G, et al. Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stress. Free Radic Biol Med. 2006;41(6):874–85.PubMedCrossRefGoogle Scholar
  59. Nilsonne G, et al. Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure. J Exp Clin Cancer Res. 2009;28:92.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Olm E, et al. Extracellular thiol-assisted selenium uptake dependent on the x(c)- cystine transporter explains the cancer-specific cytotoxicity of selenite. Proc Natl Acad Sci U S A. 2009a;106(27):11400–5.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Olm E, et al. Selenite is a potent cytotoxic agent for human primary AML cells. Cancer Lett. 2009b;282(1):116–23.PubMedCrossRefGoogle Scholar
  62. Painter EP. The chemistry and toxicity of selenium compounds, with special reference to the selenium problem. Chem Rev. 1941;28(2):179–213.CrossRefGoogle Scholar
  63. Pan MH, et al. Se-methylselenocysteine inhibits lipopolysaccharide-induced NF-kappaB activation and iNOS induction in RAW 264.7 murine macrophages. Mol Nutr Food Res. 2011;55(5):723–32.PubMedCrossRefGoogle Scholar
  64. Park SH, et al. Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species. Toxicol Lett. 2012a;212(3):252–61.PubMedCrossRefGoogle Scholar
  65. Park JS, et al. The effects of selenium on tumor growth in epithelial ovarian carcinoma. J Gynecol Oncol. 2012b;23(3):190–6.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Pinto JT, et al. Chemopreventive mechanisms of alpha-keto acid metabolites of naturally occurring organoselenium compounds. Amino Acids. 2011;41(1):29–41.PubMedCrossRefGoogle Scholar
  67. Ravn-Haren G, et al. Effect of long-term selenium yeast intervention on activity and gene expression of antioxidant and xenobiotic metabolising enzymes in healthy elderly volunteers from the Danish Prevention of Cancer by Intervention by Selenium (PRECISE) pilot study. Br J Nutr. 2008;99(6):1190–8.PubMedCrossRefGoogle Scholar
  68. Ray PD, Huang B-W, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24(5):981–90.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Rooseboom M, et al. Evaluation of the kinetics of beta-elimination reactions of selenocysteine Se-conjugates in human renal cytosol: possible implications for the use as kidney selective prodrugs. J Pharmacol Exp Ther. 2000;294(2):762–9.PubMedGoogle Scholar
  70. Rooseboom M, et al. Tissue distribution of cytosolic beta-elimination reactions of selenocysteine Se-conjugates in rat and human. Chem Biol Interact. 2002;140(3):243–64.PubMedCrossRefGoogle Scholar
  71. Rossi F, et al. Crystal structure of human kynurenine aminotransferase I. J Biol Chem. 2004;279(48):50214–20.PubMedCrossRefGoogle Scholar
  72. Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet. 1977;1(8010):549–50.CrossRefGoogle Scholar
  73. Scharrer E, Senn E, Wolffram S. Stimulation of mucosal uptake of selenium from selenite by some thiols at various sites of rat intestine. Biol Trace Elem Res. 1992;33(1):109–20.PubMedCrossRefGoogle Scholar
  74. Seko Y, Imura N. Active oxygen generation as a possible mechanism of selenium toxicity. Biomed Environ Sci. 1997;10(2–3):333–9.PubMedGoogle Scholar
  75. Shamberger RJ, Frost DV. Possible protective effect of selenium against human cancer. Can Med Assoc J. 1969;100(14):682.PubMedPubMedCentralGoogle Scholar
  76. Shen HM, Yang CF, Ong CN. Sodium selenite-induced oxidative stress and apoptosis in human hepatoma HepG2 cells. Int J Cancer. 1999;81(5):820–8.PubMedCrossRefGoogle Scholar
  77. Sieja K, Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol. 2004;93(2):320–7.PubMedCrossRefGoogle Scholar
  78. Sinha R, et al. Effects of naturally occurring and synthetic organoselenium compounds on protein profiling in androgen responsive and androgen independent human prostate cancer cells. Nutr Cancer. 2008;60(2):267–75.PubMedCrossRefGoogle Scholar
  79. Spyrou G, et al. AP-1 DNA-binding activity is inhibited by selenite and selenodiglutathione. FEBS Lett. 1995;368(1):59–63.PubMedCrossRefGoogle Scholar
  80. Stevens JL, Robbins JD, Byrd RA. A purified cysteine conjugate beta-lyase from rat kidney cytosol. Requirement for an alpha-keto acid or an amino acid oxidase for activity and identity with soluble glutamine transaminase K. J Biol Chem. 1986;261(33):15529–37.PubMedGoogle Scholar
  81. Tarze A, et al. Extracellular production of hydrogen selenide accounts for thiol-assisted toxicity of selenite against Saccharomyces cerevisiae. J Biol Chem. 2007;282(12):8759–67.PubMedCrossRefGoogle Scholar
  82. Tung YC, et al. Se-Methyl-L-selenocysteine Induces Apoptosis via Endoplasmic Reticulum Stress and the Death Receptor Pathway in Human Colon Adenocarcinoma COLO 205 Cells. J Agric Food Chem. 2015;63(20):5008–16.PubMedCrossRefGoogle Scholar
  83. Vadgama J, et al. Effect of selenium in combination with adriamycin or taxol on. Anticancer Res. 2000;20:1391–414.PubMedGoogle Scholar
  84. Vadhanavikit S, Ip C, Ganther HE. Metabolites of sodium selenite and methylated selenium compounds administered at cancer chemoprevention levels in the rat. Xenobiotica. 1993;23(7):731–45.PubMedCrossRefGoogle Scholar
  85. Vyas D, Laput G, Vyas AK. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther. 2014;7:1015.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Wallenberg M, et al. Selenium induces a multi-targeted cell death process in addition to ROS formation. J Cell Mol Med. 2014;18(4):671–84.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Wang S, et al. Dose-dependent effects of selenite (Se4+) on arsenite (As3+)-induced apoptosis and differentiation in acute promyelocytic leukemia cells. Cell Death Dis. 2015;6(1):e1596.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Watson-Williams E. A preliminary note on the treatment of inoperable carcinoma with selenium. Br Med J. 1919;2(3067):463–4.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Whanger PD. Selenium and its relationship to cancer: an update. Br J Nutr. 2004;91(1):11–28.PubMedCrossRefGoogle Scholar
  90. Würmli R, et al. Stimulation of mucosal uptake of selenium from selenite by L-cysteine in sheep small intestine. Biol Trace Elem Res. 1989;20(1):75–85.PubMedCrossRefGoogle Scholar
  91. Yang H, Jia X. Safety evaluation of Se-methylselenocysteine as nutritional selenium supplement: acute toxicity, genotoxicity and subchronic toxicity. Regul Toxicol Pharmacol. 2014;70(3):720–7.PubMedCrossRefGoogle Scholar
  92. Zeng H. Selenium as an essential micronutrient: roles in cell cycle and apoptosis. Molecules. 2009;14(3):1263–78.PubMedCrossRefGoogle Scholar
  93. Zeng H, et al. The selenium metabolite methylselenol inhibits the migration and invasion potential of HT1080 tumor cells. J Nutr. 2006;136(6):1528–32.PubMedCrossRefGoogle Scholar
  94. Zeng H, Wu M, Botnen JH. Methylselenol, a selenium metabolite, induces cell cycle arrest in G1 phase and apoptosis via the extracellular-regulated kinase 1/2 pathway and other cancer signaling genes. J Nutr. 2009;139(9):1613–8.PubMedCrossRefGoogle Scholar
  95. Zhao R, et al. Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells. Cancer Res. 2006;66(4):2296–304.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Zhong W, Oberley TD. Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line. Cancer Res. 2001;61(19):7071–8.PubMedGoogle Scholar
  97. Zuo L, et al. Sodium selenite induces apoptosis in acute promyelocytic leukemia-derived NB4 cells by a caspase-3-dependent mechanism and a redox pathway different from that of arsenic trioxide. Ann Hematol. 2004;83(12):751–8.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pathology F42, Department of Laboratory MedicineKarolinska Institutet, Karolinska University Hospital HuddingeStockholmSweden

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