A chemical screen identifies small molecules that regulate hepcidin expression

Blood Cells, Molecules, and Diseases

Volumn 53, Issue 4, 2014, Pages 231-240

  Gaun, Vera ^a,b   Patchen, Bonnie ^a,b   Volovetz, Josephine ^a,b   Zhen, Aileen W ^a,b   Andreev, Aleksandr ^a,b   Pollastri, Michael P ^c   Fraenkel, Paula G ^a,b  

^a BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c NORTHEASTERN UNIVERSITY   (United States)

Author keywords

Bone morphogenic protein; Hemochromatosis; Interleukin 6; Stat3; Thalassemia

Indexed keywords

10058 F 4; 5 [5 (4 FLUORO 2 HYDROXYPHENYL)FURFURYLIDENE] 2,4 THIAZOLIDINEDIONE; 6,7 DIMETHOXY 2 PHENYLQUINOXALINE; 9 AMINOCRIDINE; AMLEXANOX; BONE MORPHOGENETIC PROTEIN; DAUNORUBICIN; ETHACRIDINE LACTATE; GTP 14564; HEMATOLOGIC AGENT; HEPCIDIN; IPRIFLAVONE; LANSOPRAZOLE; LEFLUNOMIDE; ORANTINIB; PHENAZOPYRIDINE; PTEROSTILBENE; SB 204741; SMAD1 PROTEIN; SMAD5 PROTEIN; SMAD8 PROTEIN; STAT3 PROTEIN; UNCLASSIFIED DRUG; VORINOSTAT; HAMP PROTEIN, HUMAN; HYBRID PROTEIN; LUCIFERASE; MOLECULAR LIBRARY; SMAD PROTEIN; STAT3 PROTEIN, HUMAN;

ARTICLE; CELL VIABILITY; CONTROLLED STUDY; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG SCREENING; FLUORESCENCE ANALYSIS; GENE EXPRESSION; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; VALIDATION STUDY; AGONISTS; ANTAGONISTS AND INHIBITORS; CELL SURVIVAL; CHEMICAL DATABASE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETIC TRANSFECTION; GENETICS; HEPG2 CELL LINE; METABOLISM; MOLECULAR LIBRARY; PHARMACOLOGY; PLASMID; PROMOTER REGION; REPORTER GENE;

BONE MORPHOGENETIC PROTEINS; CELL SURVIVAL; DATABASES, CHEMICAL; DRUG DISCOVERY; GENE EXPRESSION REGULATION; GENES, REPORTER; HEP G2 CELLS; HEPCIDINS; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; LUCIFERASES; PLASMIDS; PROMOTER REGIONS, GENETIC; RECOMBINANT FUSION PROTEINS; SIGNAL TRANSDUCTION; SMAD PROTEINS; SMALL MOLECULE LIBRARIES; STAT3 TRANSCRIPTION FACTOR; TRANSFECTION;

EID: 84908083483     PISSN: 10799796     EISSN: 10960961     Source Type: Journal    
DOI: 10.1016/j.bcmd.2014.06.002     Document Type: Article

References (63)

1. Ganz T., Nemeth E. Hepcidin and iron homeostasis. Biochim. Biophys. Acta 2012, 1823(9):1434-1443.
2. Collins J.F., Wessling-Resnick M., Knutson M.D. Hepcidin regulation of iron transport. J. Nutr. 2008, 138(11):2284-2288.
3. Corradini E., et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology 2011, 54(1):273-284.
4. Wang R.H., et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005, 2(6):399-409.
5. Wrighting D.M., Andrews N.C. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006, 108(9):3204-3209.
6. Nemeth E., et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306(5704):2090-2093.
7. Fraenkel P.G., et al. Ferroportin1 is required for normal iron cycling in zebrafish. J. Clin. Invest. 2005, 115(6):1532-1541.
8. Papanikolaou G., et al. Hepcidin in iron overload disorders. Blood 2005, 105(10):4103-4105.
9. Lekawanvijit S., Chattipakorn N. Iron overload thalassemic cardiomyopathy: iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity. Can. J. Cardiol. 2009, 25(4):213-218.
10. Angelucci E., et al. Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Italian Cooperative Group for Phlebotomy Treatment of Transplanted Thalassemia Patients. Blood 1997, 90(3):994-998.
11. Barton J.C. Chelation therapy for iron overload. Curr. Gastroenterol. Rep. 2007, 9(1):74-82.
12. Fung E., Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 2013, 98(11):1667-1676.
13. Nicolas G., et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat. Genet. 2003, 34(1):97-101.
14. Gardenghi S., et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J. Clin. Invest. 2010, 120(12):4466-4477.
15. Yu P.B., et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 2008, 4(1):33-41.
16. North T.E., et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 2007, 447(7147):1007-1011.
17. Cutler C., et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 2013, 122(17):3074-3081.
18. Zhen A.W., et al. The small molecule, genistein, increases hepcidin expression in human hepatocytes. Hepatology 2013, 58(4):1315-1325.
19. A new agent for the control of tinea versicolor. Acrisorcin (Akrinol). JAMA 1966, 196(11):1010.
20. Lopez-Rovira T., et al. Direct binding of Smad1 and Smad4 to two distinct motifs mediates bone morphogenetic protein-specific transcriptional activation of Id1 gene. J. Biol. Chem. 2002, 277(5):3176-3185.
21. Conidi A., et al. Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFbeta/BMP signaling in vivo. Cytokine Growth Factor Rev. 2011, 22(5-6):287-300.
22. Kersten C., et al. BMP-6 inhibits human bone marrow B lymphopoiesis-upregulation of Id1 and Id3. Exp. Hematol. 2006, 34(1):72-81.
23. Dauer D.J., et al. Stat3 regulates genes common to both wound healing and cancer. Oncogene 2005, 24(21):3397-3408.
24. Goodnough J.B., et al. Inhibition of hepcidin transcription by growth factors. Hepatology 2012, 56(1):291-299.
25. Murata K., et al. Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J. Biol. Chem. 2003, 278(35):32892-32898.
26. Kovalenko M., et al. Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res. 1994, 54(23):6106-6114.
27. Laird A.D., et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 2000, 60(15):4152-4160.
28. Verstovsek S., et al. WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation. Clin. Cancer Res. 2008, 14(3):788-796.
29. Ramos E., et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 2012, 120(18):3829-3836.
30. Fung E., et al. High-throughput screening of small molecules identifies hepcidin antagonists. Mol. Pharmacol. 2013, 83(3):681-690.
31. Cooke K.S., et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood 2013, 122(17):3054-3061.
32. Theurl I., et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood 2011, 118(18):4977-4984.
33. Thorne N., Inglese J., Auld D.S. Illuminating insights into firefly luciferase and other bioluminescent reporters used in chemical biology. Chem. Biol. 2010, 17(6):646-657.
34. Thorne N., et al. Firefly luciferase in chemical biology: a compendium of inhibitors, mechanistic evaluation of chemotypes, and suggested use as a reporter. Chem. Biol. 2012, 19(8):1060-1072.
35. Auld D.S., et al. Characterization of chemical libraries for luciferase inhibitory activity. J. Med. Chem. 2008, 51(8):2372-2386.
36. Auld D.S., et al. Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression. Proc. Natl. Acad. Sci. U. S. A. 2009, 106(9):3585-3590.
37. Thompson J.F., Hayes L.S., Lloyd D.B. Modulation of firefly luciferase stability and impact on studies of gene regulation. Gene 1991, 103(2):171-177.
38. Ise R., et al. Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett. 2005, 579(7):1732-1740.
39. Tseng C.H., et al. Synthesis and anti-osteoporotic evaluation of certain 3-amino-2-hydroxypropoxyisoflavone derivatives. Eur. J. Med. Chem. 2009, 44(9):3621-3626.
40. Zhang X., et al. Effects of ipriflavone on postmenopausal syndrome and osteoporosis. Gynecol. Endocrinol. 2010, 26(2):76-80.
41. Andrae J., Gallini R., Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008, 22(10):1276-1312.
42. Shugg R.P., et al. Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption. J. Biol. Chem. 2013, 288(49):35346-35357.
43. Gomez-Curet I., et al. c-Myc inhibition negatively impacts lymphoma growth. J. Pediatr. Surg. 2006, 41(1):207-211. (discussion 207-11).
44. Huang M.J., et al. A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia. Exp. Hematol. 2006, 34(11):1480-1489.
45. McCormack D., McFadden D. A review of pterostilbene antioxidant activity and disease modification. Oxidative Med. Cell. Longev. 2013, 2013:575482.
46. Miura K., et al. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008, 48(5):1420-1429.
47. Liu H., et al. Iron regulator hepcidin exhibits antiviral activity against hepatitis C virus. PLoS ONE 2012, 7(10):e46631.
48. He H., Lehming N. Global effects of histone modifications. Brief. Funct. Genomic Proteomic 2003, 2(3):234-243.
49. Olsen E.A., et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 2007, 25(21):3109-3115.
50. Mouta Carreira C., et al. S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro. J. Biol. Chem. 1998, 273(35):22224-22231.
51. Takagi T., Naito Y., Yoshikawa T. The expression of heme oxygenase-1 induced by lansoprazole. J. Clin. Biochem. Nutr. 2009, 45(1):9-13.
52. Xu X., et al. In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action. Biochem. Pharmacol. 1999, 58(9):1405-1413.
53. Soll C., et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology 2010, 51(4):1244-1254.
54. Ebrahimkhani M.R., et al. Stimulating healthy tissue regeneration by targeting the 5-HT(2)B receptor in chronic liver disease. Nat. Med. 2011, 17(12):1668-1673.
55. Kawaratani H., et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediat. Inflamm. 2013, 2013:495156.
56. Nitiss J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer 2009, 9(5):338-350.
57. Quotti Tubi L., et al. Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. J. Hematol. Oncol. 2013, 6:78.
58. Rudolph M.I., et al. On the mechanism of action of ethodin in inducing myometrium contractions. Gen. Pharmacol. 1997, 28(3):381-385.
59. Bernardi R., et al. Analysis of poly(ADP-ribose) glycohydrolase activity in nuclear extracts from mammalian cells. Biochim. Biophys. Acta 1997, 1338(1):60-68.
60. Erdelyi K., et al. Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cell death in oxidatively stressed A549 cells. FASEB J. 2009, 23(10):3553-3563.
61. Holahan M.L., Littman M.P., Hayes C.L. Presumptive hepatotoxicity and rhabdomyolysis secondary to phenazopyridine toxicity in a dog. J. Vet. Emerg. Crit. Care (San Antonio) 2010, 20(3):352-358.
62. Wander H.J., Pascoe D.J. Phenylazopyridine hydrochloride poisoning. Report of case and review of literature. Am. J. Dis. Child. 1965, 110:105-107.
63. von Borstel R.C., Higgins J.A. Janus carcinogens and mutagens. Mutat. Res. 1998, 402(1-2):321-329.