Cell permeable iron chelators as potential cancer chemotherapeutic agents

Cancer Investigation

Volumn 23, Issue 8, 2005, Pages 683-691

  Pahl, Paula M B ^a   Horwitz, Lawrence D ^a,b  

^a UNIVERSITY OF COLORADO   (United States)

^b UNIVERSITY OF COLORADO   (United States)

Author keywords

Cell cycle; Desferri Exochelin; Iron Chelation; Pyridoxal Isonicotinoyl Hydrazone; Redox Signaling

Indexed keywords

CYCLIN DEPENDENT KINASE; DEFERASIROX; DEFEROXAMINE; DEFERRIFERRITHIOCIN; DESFERRI EXOCHELIN; FERRIC ION; FERROUS ION; IRON CHELATING AGENT; O TRENSOX; PYRIDINE DERIVATIVE; PYRIDOXAL ISONICOTINOYLHYDRAZONE; RIBONUCLEOTIDE REDUCTASE; TACHPYRIDINE [N,N',N'' TRIS(2 PYRDIYLMETHYL) 1,3,5 TRIAMINOCYCLOHEXANE]; UNCLASSIFIED DRUG;

AEROBIC METABOLISM; BREAST ADENOCARCINOMA; CANCER GROWTH; CANCER THERAPY; CELL CYCLE REGULATION; CELL GROWTH; CELL MEMBRANE PERMEABILITY; CLINICAL TRIAL; DNA DAMAGE; DNA REPLICATION; HUMAN; IRON BINDING CAPACITY; IRON CHELATION; IRON TRANSPORT; LEUKEMIA; LIPOPHILICITY; LIVER CELL CARCINOMA; MYELOID LEUKEMIA; NEUROBLASTOMA; NONHUMAN; PRIORITY JOURNAL; PROSTATE CARCINOMA; REVIEW; TUMOR CELL;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL MEMBRANE PERMEABILITY; CELL PROLIFERATION; HUMANS; IRON; IRON CHELATING AGENTS; NEOPLASMS;

EID: 30044449567     PISSN: 07357907     EISSN: 15324192     Source Type: Journal    
DOI: 10.1080/07357900500359976     Document Type: Review

References (110)

1. Cavanaugh, P.G.; Jia, L.; Zou, Y.; Nicolson, G. L. Transferrin receptor overexpression enhances transferrin responsiveness and the metastatic growth of a rat mammary adenocarcinoma cell line. Breast Cancer Res. Treat. 1999, 56 (3), 203-217.
2. McCord, J. M. Iron, free radicals, and oxidative injury. Semin. Hematol. 1998, 35 (1), 5-12.
3. Bae, Y.S.; Kang, S.W.; Seo, M.S.; Baines, I.C.; Tekle, E.; Chock, P.B.; Rhee, S.G. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. J. Biol. Chem. 1997, 272 (1), 217-221.
4. Brown, M.R.; Miller, F.J., Jr.; Li, W.-G.; Ellingson, A.N.; Mozena, J.D.; Chatterjee, P.; Engelhardt, J.F.; Zwacka, R.M.; Oberley, L.W.; Fang, X.; Spector, A.A.; Weintraub, N.L. Overexpression of human catalase inhibits proliferation and promotes apoptosis in vascular smooth muscle cells. Circ. Res. 1999, 85 (6), 524-533.
5. 2 for platelet-derived growth factor signal transduction. Science 1995, 270 (234), 296-299.
6. Behrend, L.; Henderson, G.; Zwacka, R.M. Reactive oxygen species in oncogenic transformation. Biochem. Soc. Trans. 2003, 31 (6), 1441-1444.
7. Goldstone, S.D.; Hunt, N.H. Redox regulation of the mitogen-activated protein kinase pathway during lymphocyte activation. Biochim. Biophys. Acta 1997, 1355 (3), 353-360.
8. ras as a common signaling target of reactive free radicals and cellular redox stress. J. Biol. Chem. 1995, 270 (36), 21195-21198.
9. Templeton, D.M.; Liu, Y. Genetic regulation of cell function in response to iron overload or chelation. Biochim. Biophys. Acta 2003, 1619 (2), 113-124.
10. Sauer, H.; Wartenberg, M.; Hescheler, J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol. Biochem. 2001, 11 (4), 173-186.
11. + channels. Brit. J. Pharmacol. 1999, 126 (6), 1462-1470.
12. Szatrowski, T.P.; Nathan, C.F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991, 51 (3), 794-798.
13. Saran, M.; Michel, C.; Stettmaier, K.; Bors, W. Arguments against the significance of the Fenton reaction contributing to signal pathways under in vivo conditions. Free Radic. Res. 2000, 33 (5), 567-579.
14. Toyokuni, S. Iron and carcinogenesis: from Fenton reaction to target genes. Redox Rep. 2002, 7 (4), 189-197.
15. Jackson, J.H. Potential molecular mechanisms of oxidant-induced carcinogenesis. Environ. Health Perspect. 1994, 102 (Suppl. 10) 155-157.
16. Toyokuni, S.; Okamoto, K.; Yodoi, J.; Hiai, H. Persistent oxidative stress in cancer. FEBS Lett. 1995, 358 (1), 1-3.
17. Buss, J.L.; Greene, B.T.; Turner, J.; Torti, P.M.; Torti, S.V. Iron chelators in cancer chemotherapy. Curr. Top. Med. Chem. 2004, 4 (15), 1623-1635.
18. Sherr, C.J.; Roberts, J.M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999, 13 (12), 1501-1512.
19. Schraml, P.; Bucher, C.; Bissig, H.; Nocito, A.; Haas, P.; Wilber, K.; Seelig, S.; Kononen, J.; Mihatsch, M. J.; Dirnhofer, S.; Sauter, G. Cyclin E overexpression and amplification in human tumors. J. Pathol. 2003, 200 (3), 375-382.
20. Yam, C.H.; Fung, T.K.; Poon, R.Y.C. Cyclin A in cell cycle control and cancer. Cell. Mol. Life Sci. 2002, 59 (8), 1317-1326.
21. Lee, M.-H.; Yang, H.-Y. Negative regulators of cyclin-dependent kinases and their roles in cancers. Cell. Mol. Life Sci. 2001, 58, (12-13), 1907-1922.
22. Nevins, J.R. The Rb/E2F pathway and cancer. Hum. Mol. Genet. 2001, 10 (7), 699-703.
23. Pahl, P.M.; Yan, X.D.; Hodges, Y.K.; Rosenthal, E.A.; Horwitz, M. A.; Horwitz, L.D. An exochelin of Mycobacterium tuberculosis reversibly arrests growth of human vascular smooth muscle cells in vitro. J. Biol. Chem. 2000, 275 (23), 17821-17826.
24. Le, N.T.V.; Richardson, D.R. Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP/WAF1, but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation. Carcinogenesis 2003, 24 (6), 1045-1058.
25. Alcantara, O.; Kalidas, M.; Baltathakis, I.; Boldt, D. H. Expression of multiple genes regulating cell cycle and apoptosis in differentiating hematopoietic cells is dependent on iron. Exp. Hematol. 2001, 29 (9), 1060-1069.
26. Chaston, T.B.; Lovejoy, D.B.; Watts, R.N.; Richardson, D.R. 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. 2003, 9 (1), 402-414.
27. Kulp, K.S.; Green, S.L.; Vulliet, P.R. Iron deprivation inhibits cyclin-dependent kinase activity and decreases cyclin D/CDK4 protein levels in asynchronous MDA-MB-453 human breast cancer cells. Exp. Cell Res. 1996, 229 (1), 60-68.
28. Simonart, T.; Degraef, C.; Andrei, G.; Mosselmans, R.; Hermans, P.; Van Vooren, J.-P.; Noel, J.-C.; Boelaert, J.R.; Snoeck, R.; Heenen, M. Iron chelators inhibit the growth and induce the apoptosis of Kaposi's sarcoma cells and of their putative endothelial precursors. J. Invest. Dermatol. 2000, 115 (5), 893-900.
29. El-Deiry, W. S. Regulation of p53 downstream genes. Semin. Cancer Biol. 1998, 8 (5), 345-357.
30. Malkin, D. The role of p53 in human cancer. J. Neuro-Oncol. 2001, 51 (3), 231-243.
31. Fukuchi, K.; Tomoyasu, S.; Watanabe, H.; Kaetsu, S.; Tsuruoka, N.; Gomi, K. Iron deprivation results in an increase in p53 expression. Biol. Chem. Hoppe-Seyler 1995, 376 (10), 627-630.
32. Liang, S.; Richardson, D.R. The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. Carcinogenesis 2003, 24 (10), 1601-1614.
33. Black, J.D. Protein kinase C-mediated regulation of the cell cycle. Front. Biosci. 2000, 5, D406-123.
34. 2. Proc. Natl. Acad. Sci. USA 1997, 94 (21), 11233-11237.
35. Alcantara, O.; Javors, M; Boldt, D.H. Induction of protein kinase C mRNA in cultured lymphoblastoid T cells by iron-transferrin but not by soluble iron. Blood 1991, 77 (6), 1290-1297.
36. Phillips, J.L.; Boldt, D.H.; Harper, J. Iron-transferrin-induced increase in protein kinase C activity in CCRF-CEM cells. J. Cell. Physiol. 1987, 132 (2), 349-353.
37. Alcantara, O.; Obeid, L.; Hannun, Y.; Ponka, P.; Boldt, D.H. Regulation of protein kinase C (PKC) expression by iron: effect of different iron compounds on PKC-β and PKC-α gene expression and role of the 5′-flanking region of the PKC-β gene in the response to ferric transferrin. Blood 1994, 84 (10), 3510-3517.
38. Kuvibidila, S.R.; Kitchens, D.; Baliga, B.S. In vivo and in vitro iron deficiency reduces protein kinase C activity and translocation in murine splenic and purified T cells. J. Cell. Biochem. 1999, 74 (3), 468-478.
39. Dang, C.V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell. Biol. 1999, 19 (1), 1-11.
40. Henriksson, M.; Luscher, B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer Res. 1996, 68 109-182.
41. Blackwood, E.M.; Kretzner, L.; Eisenman, R. N. Myc and Max function as a nucleoprotein complex. Curr. Opin. Genet. Dev. 1992, 2 (2), 227-235.
42. Nesbit, C.E.; Tersak, J.M.; Prochownik, E.V. MYC oncogenes and human neoplastic disease. Oncogene 1999, 78 (19), 3004-3016.
43. Kyriakou, D.; Eliopoulos, A.G.; Papadakis, A.; Alexandrakis, M.; Eliopoulos, G.D. Decreased expression of c-myc oncoprotein by peripheral blood mononuclear cells in thalassaemia patients receiving desferrioxamine. Eur. J. Haematol. 1998, 60 (1), 21-27.
44. Tomoyasu, S.; Fukuchi, K.; Yajima, K.; Watanabe, K.; Suzuki, H.; Kawakami, K.; Gomi, K.; Tsuruoka, N. Suppression of HL-60 cell proliferation by deferoxamine: changes in c-myc expression. Anticancer Res. 1993, 13 (2), 407-410.
45. Le, N.T.V.; Richardson, D.R. Iron chelators wih high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood 2004, 104, 2967-2975.
46. Jordan, A.; Reichard, P. Ribonucleotide reductases. Annu. Rev. Biochem. 1998, 67 71-98.
47. Nyholm, S.; Mann, G.J.; Johansson, A.G.; Bergeron, R.J.; Graslund, A.; Thelander, L. Role of ribonucleotide reductase in inhibition of mammalian cell growth by potent iron chelators. J. Biol. Chem. 1993, 268 (35), 26200-26205.
48. Hodges, Y.K.; Antholine, W.E.; Horwitz, L.D. Effect on ribonucleotide reductase of novel lipophilic iron chelators: the desferri-exochelins. Biochem. Biophys. Res. Commun. 2004, 315 (3), 595-598.
49. Nocentini, G. Ribonucleotide reductase inhibitors: new strategies for cancer chemotherapy. Crit. Rev. Oncol. Hematol. 1996, 22 (2), 89-126.
50. Navarra, P.; Preziosi, P. Hydroxyurea: new insights on an old drug. Crit. Rev. Oncol. Hematol. 1999, 29 (3), 249-255.
51. Bruick, R.K. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc. Natl. Acad. Sci. USA 2000, 97 (16), 9082-9087.
52. Zhong, H.; De Marco, A.M.; Laughner, E.; Lim, M.; Hilton, D.A.; D., Z.; Buechler, P.; Isaacs, W.B.; Semenza, G.L.; Simons, J.W.; Overexpression of hypoxia-inducible factor 1α in common cancers and their metastases. Cancer Res. 1999, 59 (22), 5830-5835.
53. 2-regulated prolyl hydroxylation. Science 2001, 292 (5516), 468-472.
54. 2 sensing. Science 2001, 292 (5516), 464-468.
55. Lok, C.N.; Ponka, P. Identification of a hypoxia response element in the transferrin receptor gene. J. Biol. Chem. 1999, 274 (34), 24147-24152.
56. An, W.G.; Kanekal, M.; Simon, M.C.; Maltepe, E.; Blagosklonny, M.V.; Neckers, L. M. Stabilization of wild-type p53 by hypoxia-inducible factor 1α. Nature 1998, 392, 405-408.
57. Ravi, R.; Mookerjee, B.; Bhujwalla, Z.M.; Sutter, C.H.; Artemov, D.; Zeng, Q.; Dillehay, L.E.; Madan, A.; Semenza, G.L.; Bedi, A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev 2000, 14 (1), 34-44.
58. Kwok, J.C.; Richardson, D.R. The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit. Rev. Oncol. Hematol. 2002, 42 (1), 65-78.
59. Kawabata, H.; Germain, R.S.; Vuong, P.T.; Nakamaki, T.; Said, J.W.; Koeffler, H.P. Transferrin receptor 2-α supports growth both in iron-chelated cultured cells and in vivo. J. Biol. Chem. 2000, 275 (22), 16618-16625.
60. Gruenheid, S.; Canonne-Hergaux, R; Gauthier, S.; Hackam, D.J.; Grinstein, S.; Gros, P. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med. 1999, 189 (5), 831-841.
61. Torti, F.M.; Torti, S.V. Regulation of ferritin genes and protein. Blood 2002, 99 (10), 3505-3516.
62. Cairo, G.; Recalcati, S.; Pietrangelo, A.; Minotti, G.; The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. Free Radic. Biol. Med. 2002, 32 (12), 1237-1243.
63. Beinert, H.; Kennedy, M.C.; Aconitase, a two-faced protein: enzyme and iron regulatory factor. FASEB J 1993, 7 (15), 1442-1449.
64. Brazzolotto, X.; Andriollo, M.; Guiraud, P.; Favier, A.; Moulis, J.-M.; Interactions between doxorubicin and the human iron regulatory system. Biochim. Biophys. Acta 2003, 1593 (2-3), 209-218.
65. Hentze, M.W.; Kuhn, L.C. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc. Natl. Acad. Sci. USA 1996, 93 (16), 8175-8182.
66. Weiss, G.; Werner-Pelmayer, G.; Werner, E.R.; Grunewald, K.; Wachter, H; Hentze, M. W. Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J. Exp. Med. 1994, 180 (3), 969-976.
67. Becton, D.L.; Roberts, B. Antileukemic effects of deferoxamine on human myeloid leukemia cell lines. Cancer Res. 1989, 49 (17), 4809-4812.
68. Brodie, C.; Siriwardana, G.; Lucas, J.; Schleicher, R.; Terada, N.; Szepesi, A.; Gelfand, R.; Seligman, P. 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.
69. Lloyd, J.B.; Cable, H.; Rice-Rvans, C. Evidence that desferrioxamine cannot enter cells by passive diffusion. Biochem. Pharmacol. 1991, 41 (9), 1361-1363.
70. Hann, H.W.L.; Stahlhut, M.W.; Rubin, R.; Maddrey, W.C. Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice. Cancer 1992, 70 (8), 2051-2056.
71. Jiang, X.P.; Wang, F.; Yang, D.C.; Rlliott, R.L.; Head, J.F. Induction of apoptosis by iron depletion in the human breast cancer MCF-7 cell line and the 13762NF rat mammary adenocarcinoma in vivo. Anticancer Res. 2002, 22 (5), 2685-2692.
72. Blatt, J.; Boegel, F.; Hedlund, B.E.; Arena, V.C.; Shadduck, R.K. Failure to alter the course of acute myelogenous leukemia in the rat with subcutaneous deferoxamine. Leuk. Res. 1991, 15 (5), 391-394.
73. Simonart, T.; Boelaert, J.R.; Andrei, G.; De Clercq, R.; Snoeck, R. Iron withdrawal strategies fail to prevent the growth of SiHa-induced tumors in mice. Gynecol. Oncol. 2003, 90 (1), 91-95.
74. Selig, R.A.; White, L.; Gramacho, C.; Sterling-Levis, K.; Praser, I. W.; Naidoo, D. Failure of iron chelators to reduce tumor growth in human neuroblastoma xenografts. Cancer Res. 1998, 58 (3), 473-478.
75. Donfrancesco, A.; Deb, G.; Dominici, C.; Pileggi, D.; Castello, M.A.; Helson, L. Effects of a single course of deferoxamine in neuroblastoma patients. Cancer Res. 1990, 50 (16), 4929-4930.
76. Estrov, Z.; Tawa, A.; Wang, X.-H.; Dube, I.D.; Sulh, H.; Cohen, A.; Gelfand, E.W.; Preedman, M.H. In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood 1987, 69 (3), 757-761.
77. Dreicer, R.; Kemp, J.D.; Stegink, L.D.; Cardillo, T.; Davis, C.S.; Forest, P.K.; See, W.A.A phase II trial of deferoxamine in patients with hormone-refractory metastatic prostate cancer. Cancer Invest. 1997, 15 (4), 311-317.
78. Howland, M.A. Risks of parenteral deferoxamine for acute iron poisoning. Clin. Toxicol. 1996, 34 (5), 491-497.
79. Richardson, D.R. Analogues of pyridoxal isonicotinoyl hydrazone (PIH) as potential iron chelators for the treatment of neoplasia. Leuk. Lymphoma 1998, 31 (1-2), 47-60.
80. Richardson, D.R.; Tran, E.H.; Ponka, P. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood 1995, 86 (11), 4295-4306.
81. Buss, J.L.; Arduini, E.; Shephard, K.C.; Ponka, P. Lipophilicity of analogs of pyridoxal isonicotinoyl hydrazone (PIH) determines the efflux of iron complexes and toxicity in K562 cells. Biochem. Pharmacol. 2003, 65 (3), 349-360.
82. Richardson, D.R.; Milnes, K. 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 1997, 89, 3025-3038.
83. Gao, J.; Richardson, D.R. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agent, IV: the mechanisms involved in inhibiting cell-cycle progression. Blood 2001, 98 (3), 842-850.
84. Lovejoy, D.B.; Richardson, D.R. Novel "hybrid" iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate selective antiproliferative activity against tumor cells. Blood 2002, 100, 666-676.
85. Becker, E.M.; Lovejoy, D.B.; Greer, J.M.; Watts, R.; Richardson, D. R. Identification of the di-pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti-tumor agents. Br. J. Pharmacol. 2003, 138 (5), 819-830.
86. Chaston, T.B.; Watts, R.; Yuan, J.; Richardson, D.R. Potent antitumor activity of novel iron chelators derived from di-2-pyridylketone isonicotinoyl hydrazone involves Fenton-derived free radical generation. Clin. Canc. Res. 2004, 10, 7365-7374.
87. Yuan, J.; Lovejoy, D.B.; Richardson, D.R. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood 2004, 104, 1450-1458.
88. Bergeron, R.J.; Wiegand, J.; Dionis, J.B.; Egli-Karmakka, M.; Frei, J.; Huxley-Tencer, A.; Peter, H. H. Evaluation of desferrithiocin and its synthetic analogues as orally effective iron chelators. J. Med. Chem. 1991, 34 (7), 2072-2078.
89. Baker, E.; Wong, A.; Peter, H.; Jacobs, A. Desferrithiocin is an effective iron chelator in vivo and in vitro but ferrithiocin is toxic. Br. J. Haematol. 1992, 81 (3), 424-431.
90. Kicic, A.; Chua, A.C.G.; Baker, E. Desferrithiocin is a more potent antineoplastic agent than desferrioxamine. Br. J. Pharmacol. 2002, 135 (6), 1393-1402.
91. Kicic, A.; Chua, A.C.; Baker, E. The desferrithiocin (DFT) class of iron chelators: potential as antineoplastic agents. Anti-Cancer Drug Des. 2001, 16 (4-5), 195-207.
92. Bergeron, R.J.; Wiegand, J.; McManis, J.S.; Weimar, W.R.; Huang, G. Structure-activity relationships among desazadesferrithiocin analogues. Adv. Expt. Med. Biol. 2002, 509, 167-184.
93. Bergeron, R.J.; Huang, G.; Weimar, W.R.; Smith, R.E.; Wiegand, J.; McManis, J.S. Desferrithiocin analogue based hexacoordinate iron(III) chelators. 2003, 46 (1), 16-24.
94. Bergeron, R.J.; Wiegand, J.; McManis, J.S.; Weimar, W.R.; Park, J.-H.; Eiler-McManis, E.; Bergeron, J.; Brittenham, G.M. Partition-Variant desferrithiocin analogues:organ targeting and increased iron clearance. J. Med. Chem. 2005, 48, 821-831.
95. Torti, S.V.; Torti, F.M.; Whitman, S.P.; Brechbiel, M.W.; Park, G.; Planalp, R. P. Tumor cell cytotoxicity of a novel metal chelator. Blood 1998, 92 (4), 1384-1389.
96. Zhao, R.; Planalp, R.P.; Ma, R.; Greene, B.T.; Jones, B.T.; Brechbiel, M.W.; Torti, P.M.; Torti, S.V. Role of zinc and iron chelation in apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Biochem. Pharmacol. 2004, 67, 1677-1688.
97. Greene, B.T.; Thorburn, J.; Willingham, M.C.; Thorburn, A.; Planalp, R.P.; Brechbiel, M.W.; Jennings-Gee, J.; Wilkinson, J.I.; Torti, F.M.; Torti, S.V. Activation of caspase pathways during iron chelator-mediated apoptosis. J. Biol. Chem. 2002, 277, 25568-25575.
98. Abeysinghe, R.D.; Greene, B.T.; Haynes, R.; Willingham, M.C.; Turner, J.; Planalp, R.P.; Brechbiel, M.W.; Torti, F.M.; Torti, S.V. p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Carcinogenesis 2001, 22 (10), 1607-1614.
99. Rakba, N.; Aouad, F.; Henry, C.; Caris, C.; Morel, I.; Baret, P.; Pierre, J.-L.; Brissot, P.; Ward, R.J.; Lescoat, G.; Crichton, R.R. Iron mobilisation and cellular protection by a new synthetic chelator O-Trensox. Biochem. Pharmacol. 1998, 55 (11), 1797-1806.
100. Galanello, R.; Piga, A.; Alberti, D.; Rouan, M.-C.; Bilger, H.; Sechaud, R. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to β-thalassemia. J. Clin. Pharmacol. 2003, 43 (6), 565-572.
101. Nisbet-Brown, E.; Olivieri, N.F.; Giardina P.J.; Grady, R.W.; Neufeld, E.J.; Sechaud, R.; Krebs-Brown, A.J.; Anderson, J.R.; Alberti, D.; Sizer, K.C.; Nathan, D.G. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003, 361 (9369), 1597-1602.
102. Finch, R.A.; Liu, M.-C.; Cory, A.H.; Cory, J.G.; Sartorelli, A.C. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv. Enzyme Regul. 1999, 39, 3-12.
103. Finch, R.A.; Liu, M.-C.; Grill, S.P.; Rose, W.C.; Loomis, R.; Vasquez, K.M.; Cheng, Y.-C.; Sartorelli, A.C.; Triapine (3-aminopyridine-2-arboxaldehyde- thiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem. Pharmacol. 2000, 59(8), 983-991.
104. Gobin, J.; Moore, C.H.; Reeve, J.R., Jr.; Wong, D.K.; Gibson, B.W.; Horwitz, M.A. Iron acquisition by Mycobacterium tuberculosis: Isolation and characterization of a family of iron-binding exochelins. Proc. Natl. Acad. Sci. USA 1995, 92 (11), 5189-5193.
105. Gobin, J.; Horwitz, M.A. Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall. J. Exp. Med. 1996, 183 (4), 1527-1532.
106. Horwitz, L.D.; Sherman, N.A.; Kong, Y.; Pike, A.W.; Gobin, J.; Fennessey, P.V.; Horwitz, M.A. Lipophilic siderophores of Mycobacterium tuberculosis prevent cardiac reperfusion injury. Proc. Natl. Acad. Sci. USA 1998, 95 (9), 5263-5268.
107. Horwitz, L.D.; Wallner, J.S.; Decker, D.E.; Buxser, S.E. Efficacy of lipid soluble, membrane-protective agents against hydrogen peroxide cytotoxicity in cardiac myocytes. Free Radic. Biol. Med. 1996, 21 (6), 743-753.
108. Pahl, P.M.B.; Horwitz, M.A.; Horwitz, K.B.; Horwitz, L.D. Desferriexochelin induces death by apoptosis in human breast cancer cells but does not kill normal breast cells. Breast Cancer Res. Treat. 2001, 69 (1), 69-79.
109. Chong, T.W.; Horwitz, L.D.; Moore, J.W.; Sowter, H.M.; Harris, A. L. A mycobacterial iron chelator, desferri-exochelin, induces hypoxia-inducible factors 1 and 2, NIP3, and vascular endothelial growth factor in cancer cell lines. Cancer Res. 2002, 62 (23), 6924-6927.
110. Monks, A.; Scudiero, D.A.; Johnson, G.S.; Paull, K.D.; Sausville, E. A. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anticancer Drug Des 1997, 12 (7), 533-541.