The Combination Effect of Low-Dose Arsenic Trioxide plus Deferoxamine on Viability and Inhibiting the Proliferation of NB4 Cell Line

Document Type : Original Article (s)

Authors

1 Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran

2 Professor, Department of Hematology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran

3 Department of Hematology, Allied Medical School, Mashhad University of Medical Sciences, Mashhad, Iran

4 Associate Professor, Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Background: Acute promyelocytic leukemia (APL) is one of the most prevalent myeloid lineage leukemia. Currently-available treatment options for these patients are using all trans-retinoic acid (ATRA) and, recently, arsenic trioxide (ATO). All trans-retinoic acid may cause treatment resistance in some cases; and arsenic trioxide, in high doses, has cytotoxic effects. In our study, we determined the ability of deferoxamine (DFO) in reducing the cytotoxic effects of high doses of arsenic on NB4 cell line in the acute promyelocytic leukemia.Methods: The NB4 cell line cultured, expanded and then treated with different doses of deferoxamine (50, 100, and 200 µM) alone, and low dose of arsenic trioxide (0.5 µM) in combination with different doses of deferoxamine (50, 100, 200 µM). Proceeding cells were counted, metabolic activity was measured using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] reduction assay and cell viability was determined via trypan blue exclusion assay. The data were analyzed using the Student’s t-test method and the Excel software.Findings: Cells treated with different doses of deferoxamine, alone and in combination with arsenic trioxide, showed decrease in viability and cell activity in a dose- and time-dependent manner. Treatments with combination of 0.5 µM arsenic trioxide and 200 µM deferoxamine showed the maximum effect in decreasing viability and metabolic activity of NB4 cells; and treatments with deferoxamine alone showed the minimum effect in declining viability and metabolic activity.Conclusion: This study shows that deferoxamine has a significant effect on viability of NB4 cell line and also causes decrease in cell activity. It seems that deferoxamine is an appropriate agent for inhibition of tumor cells.

Keywords

References

  1. Rego EM, De Santis GC. Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment. Mediterr J Hematol Infect Dis 2011; 3(1): e2011048.
  2. Jovanovic JV, Rennie K, Culligan D, Peniket A, Lennard A, Harrison J, et al. Development of real-time quantitative polymerase chain reaction assays to track treatment response in retinoid resistant acute promyelocytic leukemia. Front Oncol 2011; 1: 35.
  3. Grimwade D, Mrozek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol Oncol Clin North Am 2011; 25(6): 1135-61, vii.
  4. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369(2): 111-21.
  5. Park JH, Tallman MS. Treatment of acute promyelocytic leukemia without cytotoxic chemotherapy. Oncology (Williston Park) 2011; 25(8): 733-41.
  6. Lang E, Grudic A, Pankiv S, Bruserud O, Simonsen A, Bjerkvig R, et al. The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling. Blood 2012; 120(4): 847-57.
  7. Tomita A, Kiyoi H, Naoe T. Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O 3) in acute promyelocytic leukemia. Int J Hematol 2013; 97(6): 717-25.
  8. Bergeron RJ, Wiegand J, Brittenham GM. HBED ligand: preclinical studies of a potential alternative to deferoxamine for treatment of chronic iron overload and acute iron poisoning. Blood 2002; 99(8): 3019-26.
  9. Liu ZD, Hider RC. Design of clinically useful iron(III)-selective chelators. Med Res Rev 2002; 22(1): 26-64.
  10. Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer 1994; 56(3): 364-9.
  11. Blatt J, Stitely S. Antineuroblastoma activity of desferoxamine in human cell lines. Cancer Res 1987; 47(7): 1749-50.
  12. Deugnier Y, Turlin B. Iron and hepatocellular carcinoma. J Gastroenterol Hepatol 2001; 16(5): 491-4.
  13. Lederman HM, Cohen A, Lee JW, Freedman MH, Gelfand EW. Deferoxamine: a reversible S-phase inhibitor of human lymphocyte proliferation. Blood 1984; 64(3): 748-53.
  14. Renton FJ, Jeitner TM. Cell cycle-dependent inhibition of the proliferation of human neural tumor cell lines by iron chelators. Biochem Pharmacol 1996; 51(11): 1553-61.
  15. Li J, Chen P, Sinogeeva N, Gorospe M, Wersto RP, Chrest FJ, et al. Arsenic trioxide promotes histone H3 phosphoacetylation at the chromatin of CASPASE-10 in acute promyelocytic leukemia cells. J Biol Chem 2002; 277(51): 49504-10.
  16. Zhang TC, Schmitt MT, Mumford JL. Effects of arsenic on telomerase and telomeres in relation to cell proliferation and apoptosis in human keratinocytes and leukemia cells in vitro. Carcinogenesis 2003; 24(11): 1811-7.
  17. Sanz MA, Fenaux P, Lo CF. Arsenic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence. Haematologica 2005; 90(9): 1231-5.
  18. Tanaka T, Muto N, Ido Y, Itoh N, Tanaka K. Induction of embryonal carcinoma cell differentiation by deferoxamine, a potent therapeutic iron chelator. Biochim Biophys Acta 1997; 1357(1): 91-7.
  19. Fukuchi K, Tomoyasu S, Watanabe H, Tsuruoka N, Gomi K. G1 accumulation caused by iron deprivation with deferoxamine does not accompany change of pRB status in ML-1 cells. Biochim Biophys Acta 1997; 1357(3): 297-305.
  20. Hann HW, Stahlhut MW, Hann CL. Effect of iron and desferoxamine on cell growth and in vitro ferritin synthesis in human hepatoma cell lines. Hepatology 1990; 11(4): 566-9.
  21. Donfrancesco A, Deb G, Angioni A, Maurizio C, Cozza R, Jenkner A, et al. D-CECaT: a breakthrough for patients with neuroblastoma. Anticancer Drugs 1993; 4(3): 317-21.
Journal of Isfahan Medical School
Volume 32, Issue 288 - Serial Number 288
May and June 2014
Pages 818-827

Files

History

  • Receive Date: 04 January 2014
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

Share

How to cite

Statistics