Antitumor effects of clinically used iron chelators – review of literature and our own experience

Authors: L. Křupková 1,2;  L. Rašková Kafková 1;  Z. Somíková 1;  M. Beličková 3;  P. Lužná 1,4;  J. Čermák 3;  V. Divoký 1,2
Authors‘ workplace: Ústav biologie, Lékařská fakulta Univerzity Palackého v Olomouci 1;  Hemato-onkologická klinika, Lékařská fakulta Univerzity Palackého a Fakultní nemocnice Olomouc 2;  Ústav hematologie a krevní transfuze, Praha 3;  Ústav histologie a embryologie, Lékařská fakulta Univerzity Palackého v Olomouci 4
Published in: Transfuze Hematol. dnes,21, 2015, No. 3, p. 117-125.
Category: Comprehensive Reports, Original Papers, Case Reports


Myelodysplastic syndrome represents a heterogeneous group of diseases, typically characterised by ineffective haematopoiesis and transfusion dependency. Iron chelators currently represent an important treatment modality in patients with myelodysplastic syndrome (MDS), who given the presence of anaemia, are dependent on repeated blood transfusions leading to the accumulation of toxic iron in organs. It has been shown that chelation therapy significantly improves overall survival and leukaemia-free survival in patients with MDS. Besides iron chelation, iron chelators also exhibit significant antiproliferative and pro-apoptotic effects on cancer cells. The suggested mechanisms of antitumor effects of iron chelators include inhibition of cell cycle progression, induction of endoplasmic reticulum stress, accumulation of DNA damage specifically in cancer cells and modulation of antitumor immune response. The exact mechanism of action of chelating agents on cancer cells is not yet fully understood and even our data suggest that it is likely to be very complex.

Key words:
deferoxamine mesylate, iron chelators, iron, myelodysplastic syndrome, cancer cells


1. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 2012;120(12):2454–2465.

2. Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J Clin Oncol, 2011; 29(5):504–515.

3. Temraz S, Santini V, Musallam K, Taher A. Iron overload and chela-tion therapy in myelodysplastic syndromes. Crit Rev Oncol Hematol, 2014;91(1):64–73.

4. Richardson DR. Iron chelators as therapeutic agents for the treatment of cancer. Crit Rev Oncol Hematol, 2002; 42(3):267–281.

5. Buss JL, Torti FM, Torti SV. The role of iron chelation in cancer therapy. Curr Med Chem, 2003; 10(12): 1021–1034.

6. Kalinowski DS, Richardson DR. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev, 2005;57(4):547–583.

7. Richardson DR, Kalinowski DS, Lau S, Jansson PJ, Lovejoy DB. Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochim Biophys Acta, 2009;1790(7):702–717.

8. Thelander L, Graslund A, Thelander M. Continual presence of oxygen and iron required for mammalian ribonucleotide reduction: Possible regulation mechanism. Biochem Biophys Res Commun, 1983;110(3):859–865.

9. Nyholm S, Mann GJ, Johansson AG, Bergeron RJ, Graslund A, Thelander L. Role of ribo-nucleotide reductase in inhibition of mammalian cell growth by potent iron chelators. J Biol Chem, 1993;268(35):26200–26205.

10. Lane DJ, Mills TM, Shafie NH, et al. Expanding horizons in iron chelation and the treatment of cancer: role of iron in the regulation of ER stress and the epithelial-mesenchymal transition. Biochim Biophys Acta, 2014;1845(2):166–181.

11. Chen Z, Zhang D,Yue F, Zheng M, Kovacevic Z, Richardson DR. The iron chelators Dp44mT and DFO inhibit TGF‑β‑induced epithelial-mesenchymal transition via up‑regulation of N‑Myc downstream-regulated gene 1 (NDRG1). J Biol Chem, 2012;287(21):17016–17028.

12. Trondl R, Flocke LS, Kowol CR, et al. Triapine and a more potent dimethyl derivative induce endoplasmic reticulum stress in cancer cells. Mol Pharmacol, 2014;85(3):451–459.

13. Neukirchen J, Fox F, Kündgen A, et al. Improved survival in MDS patients receiving iron chelation therapy – a matched pair analysis of 188 patients from the Düsseldorf MDS registry. Leuk Res, 2012;36(8):1067–1070.

14. Remacha ÁF, Arrizabalaga B, Villegas A, et al. Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications. Ann Hematol, 2015;94(5):779–787.

15. Eberhard Y, McDermott SP, Wang X, et al. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood, 2009;114(14):3064–3073.

16. Boelaert JR, de Locht M, Van Cutsem J, et al. Mucormycosis during deferoxamine therapy is a siderophore-mediated infection. In vitro and in vivo animal studies. J Clin Invest, 1993;91(5):1979–1986.

17. Jensen PD, Jensen IM, Ellegaard J. Desferrioxamine treatment reduces blood transfusion requirements in patients with myelodysplastic syndrome. Br J Haematol, 1992;80(1):121–124.

18. Donfrancesco A, Deb G, Dominici C, Pileggi D, Castello MA, Helson L. Effects of a single course of deferoxamine in neuroblastoma patients. Cancer Res, 1990;50(16):4929–4930.

19. Hoyes KP, Hider RC, Porter JB. Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukemia cell lines. Cancer Res, 1992;52(17):4591–4599.

20. Yang LP, Keam SJ, Keating GM. Deferasirox: a review of its use in the management of transfusional chronic iron overload. Drugs, 2007;67(15):2211–2230.

21. Cohen A, Galanello R, Piga A, Vullo C, Tricta F. A multi-center safety trial of the oral iron chelator deferiprone. Ann N Y Acad Sci, 1998;850:223–226.

22. Richardson DR, Ponka P, Baker E. The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell. Cancer Res, 1994;54(3):685–689.

23. De Domenico I, Ward DM, Kaplan J. Specific iron chelators determine the route of ferritin degradation. Blood, 2009;114(20):4546–4551.

24. Larrick JW, Cresswell P. Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J Supramol Struct, 1979;11(4):579–586.

25. Elford HL, Freese M, Passamani E, Morris HP. Ribonucleotide reductase and cell prolifera­tion. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. J Biol Chem, 1970;245:5228–5233.

26. Takeda E, Weber G. Role of ribonucleotide reductase in expression in the neoplastic program. Life Sci, 1981;28(9):1007–1014.

27. Brodie C, Siriwardana G, Lucas J, et al. Neuroblastoma sensitivity to growth inhibition by deferrioxamine: Evidence for a block in G1 phase of the cell cycle. Cancer Res, 1993;53(17):3968–3975.

28. Hileti DPP, Hoffbrand AV. Iron chelators induce apoptosis in proliferating cells. Br J Haematol, 1995;89(1):181–187.

29. 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):1553–1561.

30. Gao J, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydra­zone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell‑cycle progression. Blood, 2001;98(3):842–850.

31. Yu Y, Kovacevic Z, Richardson DR. Tuning cell cycle regulation with an iron key. Cell Cycle, 2007;6(16):1982–1994.

32. Bourougaa K, Naski N, Boularan C, et al. Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol Cell, 2010;38(1):78–88.

33. Thomas SE, Malzer E, Ordóñez A, et al. p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress. J Biol Chem, 2013;288(11):7606–7617.

34. Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell, 2014;25(5):563–573.

35. Schonthal AH. Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica (Cairo), 2012;2012:857516.

36. Schonthal AH. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol, 2013;85(5):653–666.

37. Kenific CM, Thorburn A, Debnath J. Autophagy and metastasis: another double-edged sword. Curr Opin Cell Biol, 2010;22(2):241–245.

38. Kurz T, Gustafsson B, Brunk UT. Cell sensitivity to oxidative stress is influenced by ferritin autophagy. Free Radic Biol Med, 2011;50(11):1647–1658.

39. Wu Y, Li X, Xie W, Jankovic J, Le W, Pan T. Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1 alpha and induction of autophagy in SH-SY5Y cells. Neurochem Int, 2010;57(3):198–205.

40. Pullarkat V, Meng Z, Donohue C, et al. Iron chelators induce autophagic cell death in multiple myeloma cells. Leuk Res, 2014;38(8):988–996.

41. Gutierrez E, Richardson DR, Jansson PJ. The anticancer agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes prosurvival autophagy by two mechanisms: persistent induction of autophagosome synthesis and impairment of lysosomal integrity. J Biol Chem, 2014;289(48):33568–33589.

42. Sahni S, Bae DH, Lane DJR, et al. Molecular bases of disease: the metastasis supressor, N-myc downstream-regulated gene 1 (NDRG1) inhibits stress-induced autophagy in cancer cells. J Biol Chem, 2014;289(14):9692–9709.

43. Choi EY, Kim EC, Oh HM, et al. Iron chelator triggers inflammatory signals in human intestinal epithelial cells: involvement of p38 and extracellular signal-regulated kinase signaling pathways. J Immunol, 2004;172(11):7069–7077.

44. Lee SK, Lee J, Min SK, et al. Iron chelator differentially activates macrophage inflammatory protein-3alpha/CCL20 in immortalized and malignant human oral keratinocytes. Arch Oral Biol, 2008;53(9):801–809.

45. Fan Y, Wang J, Wei L, He B, Wang C, Wang B. Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-κB pathway. Int J Cardiol, 2011;152(1):49–55.

46. Lee SK, Jang HJ, Lee HJ, et al. p38 and ERK MAP kinase mediates iron chelator‑induced apoptosis and ‑suppressed differentiation in immortalized and malignant human oral keratinocytes. Life Sci, 2006;79:1419–1427.

47. Horvathova M, Ponka P, Divoky V. Molecular basis of hereditary iron homeostasis defects. Hematology, 2010;15(2):96–111.

48. Koledova Z, Kafkova LR, Krämer A, Divoky V. DNA damage-induced degradation of Cdc25A does not lead to inhibition of Cdk2 activity in mouse embryonic stem cells. Stem Cells, 2010;28(3):450–461.

49. Cermak J, Jonasova A, Vondrakova J, et al. Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome. Hemoglobin, 2011;35(3):217–227.

50. Takacova S, Slany R, Bartkova J, et al. DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo. Cancer Cell, 2012;21(4):517–531.

Haematology Internal medicine Clinical oncology
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account