The iron chelator, deferasirox, as a novel strategy for cancer treatment: Oral activity against human lung tumor xenografts and molecular mechanism of actions

Molecular Pharmacology

Volumn 83, Issue 1, 2013, Pages 179-190

  Lui, Goldie Y L ^a   Obeidy, Peyman ^a   Ford, Samuel J ^b   Tselepis, Chris ^b   Sharp, Danae M ^a   Jansson, Patric J ^a   Kalinowski, Danuta S ^a   Kovacevic, Zaklina ^a   Lovejoy, David B ^a   Richardson, Des R ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

^b UNIVERSITY OF BIRMINGHAM   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE 3; COPPER; CYCLIN D1; CYCLIN DEPENDENT KINASE INHIBITOR 1; DEFERASIROX; IRON; MYC PROTEIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; TRANSFERRIN; ZINC;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CELL CYCLE REGULATION; CONTROLLED STUDY; FEMALE; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IRON CHELATION; IRON TRANSPORT; LUNG CARCINOMA; METASTASIS; MOLECULAR MECHANICS; MOUSE; NEUROEPITHELIOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SOLID TUMOR; TUMOR XENOGRAFT;

ADMINISTRATION, ORAL; ANIMALS; ANTIGENS, CD; ANTINEOPLASTIC AGENTS; APOPTOSIS; BENZOATES; CELL CYCLE; CELL LINE, TUMOR; COPPER; CYCLIN D1; CYCLIN-DEPENDENT KINASE INHIBITOR P21; FEMALE; HUMANS; IRON; IRON CHELATING AGENTS; LUNG NEOPLASMS; MICE; MICE, INBRED BALB C; MICE, NUDE; NEOPLASM METASTASIS; NEOPLASM TRANSPLANTATION; NEUROECTODERMAL TUMORS, PRIMITIVE, PERIPHERAL; PROTEIN-SERINE-THREONINE KINASES; RECEPTORS, TRANSFERRIN; SMALL CELL LUNG CARCINOMA; TRANSPLANTATION, HETEROLOGOUS; TRIAZOLES; ZINC;

EID: 84871575976     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.112.081893     Document Type: Article

References (61)

1. Baker E, Richardson D, Gross S, and Ponka P (1992) Evaluation of the iron chelation potential of hydrazones of pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde using the hepatocyte in culture. Hepatology 15:492-501.
2. Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, and Watabe M et al. (2003) The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res 63:1731-1736. (Pubitemid 36460828)
3. Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D, Commes T, Watabe M, and Gross SC et al. (2004) Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene 23:5675-5681. (Pubitemid 39093045)
4. Becker E and Richardson DR (1999) Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs. J Lab Clin Med 134:510-521. (Pubitemid 29530701)
5. Bendová P, Macková E, Haškova P, Vávrová A, Jirkovský E, Štěrba M, Popelová O,Kovaříková P, and Vávrová K et al. (2010) Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury. Chem Res Toxicol 23:1105-1114.
6. Brard L, Granai CO, and Swamy N (2006) Iron chelators deferoxamine and diethylenetriamine pentaacetic acid induce apoptosis in ovarian carcinoma. Gynecol Oncol 100:116-127. (Pubitemid 41815060)
7. Broto P, Moreau G, and Vandycke C (1984) Molecular structures: perception, autocorrelation descriptor and SAR studies. System of atomic contributions for the calculation of the n-octanol/water partition coefficients. Eur J Med Chem 19:71-78. (Pubitemid 14156802)
8. Cappellini MD (2007) Exjade(R) (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion. Ther Clin Risk Manag 3:291-299.
9. Chaston TB, Lovejoy DB, Watts RN, and Richardson DR (2003) Examination of the antiproliferative activity of iron chelators: multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin Cancer Res 9:402-414. (Pubitemid 36109758)
10. Chua AC, Graham RM, Trinder D, and Olynyk JK (2007) The regulation of cellular iron metabolism. Crit Rev Clin Lab Sci 44:413-459. (Pubitemid 47619398)
11. Finkenstedt A, Wolf E, Höfner E, Gasser BI, Bösch S, Bakry R, Creus M, Kremser C, Schocke M, and Theurl M et al. (2010) Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation. J Hepatol 53:1101-1107.
12. Fu D and Richardson DR (2007) Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion. Blood 110:752-761. (Pubitemid 47105414)
13. Fukushima T, Kawabata H, Nakamura T, Iwao H, Nakajima A, Miki M, Sakai T, Sawaki T, Fujita Y, and Tanaka M et al. (2011) Iron chelation therapy with deferasirox induced complete remission in a patient with chemotherapy-resistant acute monocytic leukemia. Anticancer Res 31:1741-1744.
14. Gao J and Richardson DR (2001) 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 98:842-850.
15. Ghose AK and Crippen GM (1987) Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions. J Chem Inf Comput Sci 27:21-35.
16. Greene BT, Thorburn J, Willingham MC, Thorburn A, Planalp RP, Brechbiel MW, Jennings-Gee J, Wilkinson J, 4th, Torti FM, and Torti SV (2002) Activation of caspase pathways during iron chelator-mediated apoptosis. J Biol Chem 277:25568-25575. (Pubitemid 34951873)
17. Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, and Pardee AB (2000) Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res 60:749-755. (Pubitemid 30094577)
18. Harper JW, Adami GR, Wei N, Keyomarsi K, and Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805-816. (Pubitemid 23346377)
19. Hašková P, Koubková L, Vávrová A, Macková E, Hrušková K, Kovaříková P, VávrováK, and Simůnek T (2011) Comparison of various iron chelators used in clinical practice as protecting agents against catecholamine-induced oxidative injury and cardiotoxicity. Toxicology 289:122-131.
20. Hentze MW and Kühn LC (1996) Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA 93:8175-8182. (Pubitemid 26269529)
21. Hershko C, Konijn AM, Nick HP, Breuer W, Cabantchik ZI, and Link G (2001) ICL670A: a new synthetic oral chelator: evaluation in hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores and in iron-loaded rat heart cells in culture. Blood 97:1115-1122. (Pubitemid 32154301)
22. Hosoi F, Izumi H, Kawahara A, Murakami Y, Kinoshita H, Kage M, Nishio K, Kohno K, Kuwano M, and Ono M (2009) N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of kappaB kinase beta expression. Cancer Res 69:4983- 4991.
23. Ibrahim AS, Gebermariam T, Fu Y, Lin L, Husseiny MI, French SW, Schwartz J, Skory CD, Edwards JE, Jr, and Spellberg BJ (2007) The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest 117:2649-2657. (Pubitemid 47494365)
24. Kalinowski DS and Richardson DR (2005) The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev 57:547-583. (Pubitemid 43036441)
25. Kim JL, Kang HN, Kang MH, Yoo YA, Kim JS, and Choi CW (2011) The oral iron chelator deferasirox induces apoptosis in myeloid leukemia cells by targeting caspase. Acta Haematol 126:241-245.
26. Knox JJ, Hotte SJ, Kollmannsberger C, Winquist E, Fisher B, and Eisenhauer EA (2007) Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). Invest New Drugs 25:471-477. (Pubitemid 47222906)
27. Kornmann M, Ishiwata T, Itakura J, Tangvoranuntakul P, Beger HG, and Korc M (1998) Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival. Oncology 55:363-369. (Pubitemid 28279682)
28. Kovacevic Z, Chikhani S, Lovejoy DB, and Richardson DR (2011a) Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: a new strategy for the treatment of pancreatic cancer. Mol Pharmacol 80:598-609.
29. Kovacevic Z and Richardson DR (2006) The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis 27:2355-2366. (Pubitemid 44884092)
30. Kovacevic Z, Sivagurunathan S, Mangs H, Chikhani S, Zhang D, and Richardson DR (2011b) The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), upregulates p21 via p53-independent mechanisms. Carcinogenesis 32:732-740.
31. Kwok JC and Richardson DR (2002) The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit Rev Oncol Hematol 42:65-78. (Pubitemid 34229148)
32. Le NT and Richardson DR (2004) Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood 104:2967-2975. (Pubitemid 39434989)
33. Lescoat G, Chantrel-Groussard K, Pasdeloup N, Nick H, Brissot P, and Gaboriau F (2007) Antiproliferative and apoptotic effects in rat and human hepatoma cell cultures of the orally active iron chelator ICL670 compared to CP20: a possible relationship with polyamine metabolism. Cell Prolif 40:755-767. (Pubitemid 47416557)
34. Lovejoy DB and Richardson DR (2002) Novel "hybrid" iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells. Blood 100:666-676. (Pubitemid 34761134)
35. Lovejoy DB, Sharp DM, Seebacher N, Obeidy P, Prichard T, Stefani C, Basha MT, Sharpe PC, Jansson PJ, and Kalinowski DS et al. (2012) Novel second-generation di-2-pyridylketone thiosemicarbazones show synergism with standard chemotherapeutics and demonstrate potent activity against lung cancer xenografts after oral and intravenous administration in vivo. J Med Chem 55:7230-7244.
36. Merlot AM, Kalinowski DS, and Richardson DR (2012) Novel chelators for cancer treatment: where are we now? Antioxid Redox Signal DOI: 10.1089/ars.2012.4540 [published ahead of print].
37. Messa E, Carturan S, Maffe C, Pautasso M, Bracco E, Roetto A, Messa F, Arruga F, Defilippi I, and Rosso V et al. (2010) Deferasirox is a powerful NF-kappaB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging. Haematologica 95:1308-1316.
38. Mishina T, Dosaka-Akita H, Kinoshita I, Hommura F, Morikawa T, Katoh H, and Kawakami Y (1999) Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome. Br J Cancer 80:1289-1295. (Pubitemid 29264094)
39. Murakami Y, Hosoi F, Izumi H, Maruyama Y, Ureshino H, Watari K, Kohno K, Kuwano M, and Ono M (2010) Identification of sites subjected to serine/threonine phosphorylation by SGK1 affecting N-myc downstream-regulated gene 1 (NDRG1)/Cap43-dependent suppression of angiogenic CXC chemokine expression in human pancreatic cancer cells. Biochem Biophys Res Commun 396:376-381.
40. Nick H, Allegrini PR, Fozard L, Junker U, Rojkjaer L, Salie R, Niederkofler V, and O'Reilly T (2009) Deferasirox reduces iron overload in a murine model of juvenile hemochromatosis. Exp Biol Med (Maywood) 234:492-503.
41. Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, Krebs-Brown AJ, Anderson JR, Alberti D, and Sizer KC et al. (2003) Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 361:1597-1602. (Pubitemid 36578996)
42. Nurtjahja-Tjendraputra E, Fu D, Phang JM, and Richardson DR (2007) Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression. Blood 109:4045-4054. (Pubitemid 46641760)
43. Ohyashiki JH, Kobayashi C, Hamamura R, Okabe S, Tauchi T, and Ohyashiki K (2009) The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. Cancer Sci 100:970-977.
44. Olivieri NF and Brittenham GM (1997) Iron-chelating therapy and the treatment of thalassemia. Blood 89:739-761. (Pubitemid 27121266)
45. Porter JB (2009) Optimizing iron chelation strategies in beta-thalassaemia major. Blood Rev 23 (Suppl 1):S3-S7.
46. Richardson DR and Baker E (1992) Intermediate steps in cellular iron uptake from transferrin. Detection of a cytoplasmic pool of iron, free of transferrin. J Biol Chem 267:21384-21389.
47. Richardson DR and Milnes K (1997) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents II: the mechanism of action of ligands derived from salicylaldehyde benzoyl hydrazone and 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone. Blood 89:3025-3038. (Pubitemid 27172591)
48. Richardson DR, Tran EH, and Ponka P (1995) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood 86:4295-4306.
49. Sato T, Kobune M, Murase K, Kado Y, Okamoto T, Tanaka S, Kikuchi S, Nagashima H, Kawano Y, and Takada K et al. (2011) Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis. Hepatol Res 41:660-667.
50. Steinhauser S, Heinz U, Bartholomä M, Weyhermüller T, Nick H, and Hegetschweiler K (2004) Complex formation of ICL670 and related ligands with FeIII and FeII. Eur J Inorg Chem (21):4177-4192.
51. Suryo Rahmanto Y and Richardson DR (2009) Generation and characterization of transgenic mice hyper-expressing melanoma tumour antigen p97 (Melanotransferrin): no overt alteration in phenotype. Biochim Biophys Acta 1793:1210-1217.
52. Suttie AW (2006) Histopathology of the spleen. Toxicol Pathol 34:466-503.
53. Tang DG and Porter AT (1996) Apoptosis: A Current Molecular Analysis. Pathol Oncol Res 2:117-131.
54. Viswanadhan VN, Ghose AK, Revankar GR, and Robins RK (1989) Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics. J Chem Inf Comput Sci 29:163-172.
55. Wang D, Liu YF, and Wang YC (2006) [Deferoxamine induces apoptosis of HL-60 cells by activating caspase-3]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 14:485-487.
56. Whitnall M, Howard J, Ponka P, and Richardson DR (2006) A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA 103:14901-14906. (Pubitemid 44527826)
57. Yen Y, Margolin K, Doroshow J, Fishman M, Johnson B, Clairmont C, Sullivan D, and Sznol M (2004) A phase I trial of 3-aminopyridine-2- carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother Pharmacol 54:331-342. (Pubitemid 39304428)
58. Yu Y, Kovacevic Z, and Richardson DR (2007) Tuning cell cycle regulation with an iron key. Cell Cycle 6:1982-1994. (Pubitemid 47327885)
59. Yu Y, Suryo Rahmanto Y, Hawkins CL, and Richardson DR (2011b) The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3- thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity. Mol Pharmacol 79:921-931.
60. Yu Y, Suryo Rahmanto Y, and Richardson DR (2012a) Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy. Br J Pharmacol 165:148-166.
61. Yuan J, Lovejoy DB, and Richardson DR (2004) Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood 104:1450-1458. (Pubitemid 39166524)