Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract

World Journal of Gastroenterology

Volumn 20, Issue 40, 2014, Pages 14778-14786

  Pines, Mark ^a  

^a VOLCANI CENTER   (Israel)

Author keywords

Cancer; Extracellular matrix; Myofibroblast; Stellate cell; Transforming growth factor

Indexed keywords

HALOFUGINONE; ANTINEOPLASTIC AGENT; GASTROINTESTINAL AGENT; PIPERIDINE DERIVATIVE; QUINAZOLINONE DERIVATIVE;

CANCER CHEMOTHERAPY; CYSTIC FIBROSIS; DIGESTIVE SYSTEM CANCER; DRUG MECHANISM; ESOPHAGUS DISEASE; ESOPHAGUS FIBROSIS; FIBROSIS; HUMAN; LIVER FIBROSIS; LIVER REGENERATION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); REVIEW; TISSUE REGENERATION; ANIMAL; DIGESTIVE SYSTEM DISEASES; DIGESTIVE SYSTEM NEOPLASMS; DRUG EFFECTS; GASTROINTESTINAL TRACT; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; REGENERATION; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; DIGESTIVE SYSTEM DISEASES; DIGESTIVE SYSTEM NEOPLASMS; FIBROSIS; GASTROINTESTINAL AGENTS; GASTROINTESTINAL TRACT; HUMANS; PIPERIDINES; QUINAZOLINONES; REGENERATION; SIGNAL TRANSDUCTION;

EID: 84910685554     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i40.14778     Document Type: Review

References (94)

1. Zeisberg M, Kalluri R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am J Physiol Cell Physiol 2013; 304: C216-C225 [PMID: 23255577 DOI: 10.1152/ajp-cell.00328.2012]
2. Kramann R, DiRocco DP, Humphreys BD. Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. J Pathol 2013; 231: 273-289 [PMID: 24006178 DOI: 10.1002/path.4253]
3. Magness ST, Bataller R, Yang L, Brenner DA. A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology 2004; 40: 1151-1159 [PMID: 15389867 DOI: 10.1002/hep.20427]
4. Verrecchia F, Mauviel A. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 2002; 118: 211-215 [PMID: 11841535 DOI: 10.1046/j.1523-1747.2002.01641]
5. Takaya Y, Tasaka H, Chiba T, Uwai K, Tanitsu M, Kim HS, Wataya Y, Miura M, Takeshita M, Oshima Y. New type of febrifugine analogues, bearing a quinolizidine moiety, show potent antimalarial activity against Plasmodium malaria parasite. J Med Chem 1999; 42: 3163-3166 [PMID: 10447961 DOI: 10.1021/jm990131e]
6. McLaughlin NP, Evans P, Pines M. The chemistry and biology of febrifugine and halofuginone. Bioorg Med Chem 2014; 22: 1993-2004 [PMID: 24650700 DOI: 10.1016/j.bmc.2014.02.040]
7. Pines M, Nagler A. Halofuginone: a novel antifibrotic therapy. Gen Pharmacol 1998; 30: 445-450 [PMID: 9522159]
8. Pines M, Vlodavsky I, Nagler A. Halofuginone: From veterinary use to human therapy. Drug Develop Res 2000; 50: 371-378
9. Pines M. Targeting TGFβ signaling to inhibit fibroblast activation as a therapy for fibrosis and cancer: effect of halofuginone. Expert Opin Drug Discov 2008; 3: 11-20 [PMID: 23480137 DOI: 10.1517/17460441.3.1.11]
10. Halevy O, Nagler A, Levi-Schaffer F, Genina O, Pines M. Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients: effect of halofuginone. Biochem Pharmacol 1996; 52: 1057-1063 [PMID: 8831725]
11. Pines M, Domb A, Ohana M, Inbar J, Genina O, Alexiev R, Nagler A. Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone. Biochem Pharmacol 2001; 62: 1221-1227 [PMID: 11705455]
12. Turgeman T, Hagai Y, Huebner K, Jassal DS, Anderson JE, Genin O, Nagler A, Halevy O, Pines M. Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginone. Neuromuscul Disord 2008; 18: 857-868 [PMID: 18672370 DOI: 10.1016/j.nmd.2008.06.386]
13. McGaha TL, Phelps RG, Spiera H, Bona C. Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-beta-mediated Smad3 activation in fibroblasts. J Invest Dermatol 2002; 118: 461-470 [PMID: 11874485 DOI: 10.1046/j.0022-202x.2001.01690]
14. Zion O, Genin O, Kawada N, Yoshizato K, Roffe S, Nagler A, Iovanna JL, Halevy O, Pines M. Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas 2009; 38: 427-435 [PMID: 19188864 DOI: 10.1097/MPA.0b013e3181967670]
15. Gnainsky Y, Kushnirsky Z, Bilu G, Hagai Y, Genina O, Volpin H, Bruck R, Spira G, Nagler A, Kawada N, Yoshizato K, Reinhardt DP, Libermann TA, Pines M. Gene expression during chemically induced liver fibrosis: effect of halofuginone on TGF-beta signaling. Cell Tissue Res 2007; 328: 153-166 [PMID: 17180598]
16. Roffe S, Hagai Y, Pines M, Halevy O. Halofuginone inhibits Smad3 phosphorylation via the PI3K/Akt and MAPK/ERK pathways in muscle cells: effect on myotube fusion. Exp Cell Res 2010; 316: 1061-1069 [PMID: 20060825 DOI: 10.1016/j.yexcr.2010.01.003]
17. Zeplin PH. Halofuginone down-regulates Smad3 expression and inhibits the TGFbeta-induced expression of fibrotic markers in human corneal fibroblasts. Ann Plast Surg 2014; 72: 489 [PMID: 23845969 DOI: 10.1097/SAP.0b013e31828a49e3]
18. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 2009; 324: 1334-1338 [PMID: 19498172 DOI: 10.1126/science.1172638]
19. Pietrella D, Rachini A, Pines M, Pandey N, Mosci P, Bistoni F, d'Enfert C, Vecchiarelli A. Th17 cells and IL-17 in protective immunity to vaginal candidiasis. PLoS One 2011; 6: e22770 [PMID: 21818387 DOI: 10.1371/journal.pone.0022770]
20. Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M, Yum J, Kim YJ, Lee HK, Cortese JF, Wirth DF, Dignam JD, Rao A, Yeo CY, Mazitschek R, Whitman M. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol 2012; 8: 311-317 [PMID: 22327401 DOI: 10.1038/nchembio.790]
21. Zhou H, Sun L, Yang XL, Schimmel P. ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature 2013; 494: 121-124 [PMID: 23263184 DOI: 10.1038/nature11774]
22. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006; 441: 231-234 [PMID: 16648837 DOI: 10.1038/nature04754]
23. Das J, Ren G, Zhang L, Roberts AI, Zhao X, Bothwell AL, Van Kaer L, Shi Y, Das G. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 2009; 206: 2407-2416 [PMID: 19808254 DOI: 10.1084/jem.20082286]
24. Nunes AC, Romãozinho JM, Pontes JM, Rodrigues V, Ferreira M, Gomes D, Freitas D. Risk factors for stricture development after caustic ingestion. Hepatogastroenterology 2002; 49: 1563-1566 [PMID: 12397736]
25. Contini S, Scarpignato C. Caustic injury of the upper gastrointestinal tract: a comprehensive review. World J Gastroenterol 2013; 19: 3918-3930 [PMID: 23840136 DOI: 10.3748/wjg.v19.i25.3918]
26. Prisman E, Miles BA, Genden EM. Prevention and management of treatment-induced pharyngo-oesophageal stricture. Lancet Oncol 2013; 14: e380-e386 [PMID: 23896277 DOI: 10.1016/S1470-2045(13)70160-8]
27. Ozc¸elik MF, Pekmezci S, Saribeyoʇlu K, Unal E, Gümüştaş K, Doʇusoy G. The effect of halofuginone, a specific inhibitor of collagen type 1 synthesis, in the prevention of esophageal strictures related to caustic injury. Am J Surg 2004; 187: 257-260 [PMID: 14769315]
28. Arbell D, Udassin R, Koplewitz BZ, Ohana M, Genina O, Pines M, Nagler A. Prevention of esophageal strictures in a caustic burn model using halofuginone, an inhibitor of collagen type I synthesis. Laryngoscope 2005; 115: 1632-1635 [PMID: 16148708 DOI: 10.1097/01.mlg.0000176551.09051.f2]
29. Dabak H, Karlidag T, Akpolat N, Keles E, Alpay HC, Serin M, Kaygusuz I, Yalcin S, Isik O. The effects of methylprednisolone and halofuginone on preventing esophageal and hypopharyngeal fibrosis in delivered radiotherapy. Eur Arch Otorhinolaryngol 2010; 267: 1429-1435 [PMID: 20364346 DOI: 10.1007/s00405-010-1242-y]
30. Wu Y, Schomisch SJ, Cipriano C, Chak A, Lash RH, Ponsky JL, Marks JM. Preliminary results of antiscarring therapy in the prevention of postendoscopic esophageal mucosectomy strictures. Surg Endosc 2014; 28: 447-455 [PMID: 24100858 DOI: 10.1007/s00464-013-3210-2]
31. Nagler A, Gofrit O, Ohana M, Pode D, Genina O, Pines M. The effect of halofuginone, an inhibitor of collagen type i synthesis, on urethral stricture formation: in vivo and in vitro study in a rat model. J Urol 2000; 164: 1776-1780 [PMID: 11025768]
32. Nagler A, Rivkind AI, Raphael J, Levi-Schaffer F, Genina O, Lavelin I, Pines M. Halofuginone - an inhibitor of collagen type I synthesis - prevents postoperative formation of abdominal adhesions. Ann Surg 1998; 227: 575-582 [PMID: 9563549]
33. Washburn S, Jennell JL, Hodges SJ. Halofuginone- and chitosan-coated amnion membranes demonstrate improved abdominal adhesion prevention. ScientificWorldJournal 2010; 10: 2362-2366 [PMID: 21170487 DOI: 10.1100/tsw.2010.234]
34. Nagler A, Genina O, Lavelin I, Ohana M, Pines M. Halofuginone, an inhibitor of collagen type I synthesis, prevents postoperative adhesion formation in the rat uterine horn model. Am J Obstet Gynecol 1999; 180: 558-563 [PMID: 10076128]
35. Eliashar R, Ochana M, Maly B, Pines M, Sichel JY, Nagler A. Halofuginone prevents subglottic stenosis in a canine model. Ann Otol Rhinol Laryngol 2006; 115: 382-386 [PMID: 16739671]
36. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425-456 [PMID: 21073339 DOI: 10.1146/annurev-pathol-011110-130246]
37. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 2013; 144: 512-527 [PMID: 23313965 DOI: 10.1053/j.gastro.2013.01.002]
38. Kocabayoglu P, Friedman SL. Cellular basis of hepatic fibrosis and its role in inflammation and cancer. Front Biosci (Schol Ed) 2013; 5: 217-230 [PMID: 23277047]
39. Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 2012; 3: 344 [PMID: 22973234 DOI: 10.3389/fphys.2012.00344]
40. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88: 125-172 [PMID: 18195085 DOI: 10.1152/physrev.00013.2007]
41. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134: 1655-1669 [PMID: 18471545 DOI: 10.1053/j.gastro.2008.03.003]
42. Cohen-Naftaly M, Friedman SL. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol 2011; 4: 391-417 [PMID: 22043231 DOI: 10.1177/1756283X11413002]
43. Apte MV, Wilson JS, Lugea A, Pandol SJ. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 2013; 144: 1210-1219 [PMID: 23622130]
44. Guyot C, Lepreux S, Combe C, Doudnikoff E, Bioulac-Sage P, Balabaud C, Desmoulière A. Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved. Int J Biochem Cell Biol 2006; 38: 135-151 [PMID: 16257564]
45. Jiao J, Friedman SL, Aloman C. Hepatic fibrosis. Curr Opin Gastroenterol 2009; 25: 223-229 [PMID: 19396960]
46. Talukdar R, Tandon RK. Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol 2008; 23: 34-41 [PMID: 17995943 DOI: 10.1111/j.1440-1746.2007.05206]
47. Schuppan D, Koda M, Bauer M, Hahn EG. Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets? Acta Gastroenterol Belg 2008; 63: 366-370 [PMID: 11233519]
48. Pines M, Knopov V, Genina O, Lavelin I, Nagler A. Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis. J Hepatol 1997; 27: 391-398 [PMID: 9288615]
49. Bruck R, Genina O, Aeed H, Alexiev R, Nagler A, Avni Y, Pines M. Halofuginone to prevent and treat thioacetamideinduced liver fibrosis in rats. Hepatology 2001; 33: 379-386 [PMID: 11172339]
50. Gnainsky Y, Spira G, Paizi M, Bruck R, Nagler A, Abu-Amara SN, Geiger B, Genina O, Monsonego-Ornan E, Pines M. Halofuginone, an inhibitor of collagen synthesis by rat stellate cells, stimulates insulin-like growth factor binding protein-1 synthesis by hepatocytes. J Hepatol 2004; 40: 269-277 [PMID: 14739098]
51. Liang J, Zhang B, Shen RW, Liu JB, Gao MH, Li Y, Li YY, Zhang W. Preventive effect of halofuginone on concanavalin A-induced liver fibrosis. PLoS One 2013; 8: e82232 [PMID: 24358159 DOI: 10.1371/journal.pone.0082232]
52. Halevy O, Genin O, Barzilai-Tutsch H, Pima Y, Levi O, Moshe I, Pines M. Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone. Histol Histopathol 2013; 28: 211-226 [PMID: 23275304]
53. Nagler A, Pines M. Topical treatment of cutaneous chronic graft versus host disease with halofuginone: a novel inhibitor of collagen type I synthesis. Transplantation 1999; 68: 1806-1809 [PMID: 10609960]
54. Pines M, Snyder D, Yarkoni S, Nagler A. Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma. Biol Blood Marrow Transplant 2003; 9: 417-425 [PMID: 12869955]
55. Popov Y, Patsenker E, Bauer M, Niedobitek E, Schulze-Krebs A, Schuppan D. Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFkappaB. J Biol Chem 2006; 281: 15090-15098 [PMID: 16489207]
56. Riehle KJ, Dan YY, Campbell JS, Fausto N. New concepts in liver regeneration. J Gastroenterol Hepatol 2011; 26 Suppl 1: 203-212 [PMID: 21199532 DOI: 10.1111/j.1440-1746.2010.06539.x]
57. Duncan AW, Soto-Gutierrez A. Liver repopulation and regeneration: new approaches to old questions. Curr Opin Organ Transplant 2013; 18: 197-202 [PMID: 23425785 DOI: 10.1097/MOT.0b013e32835f07e2]
58. Moser MA, Kneteman NM, Minuk GY. Research toward safer resection of the cirrhotic liver. HPB Surg 2000; 11: 285-297 [PMID: 10674743 DOI: 10.1155/2000/31945]
59. Hsu KY, Chau GY, Lui WY, Tsay SH, King KL, Wu CW. Predicting morbidity and mortality after hepatic resection in patients with hepatocellular carcinoma: the role of Model for End-Stage Liver Disease score. World J Surg 2009; 33: 2412-2419 [PMID: 19756859 DOI: 10.1007/s00268-009-0202-4]
60. Ruzzenente A, Valdegamberi A, Campagnaro T, Conci S, Pachera S, Iacono C, Guglielmi A. Hepatocellular carcinoma in cirrhotic patients with portal hypertension: is liver resection always contraindicated? World J Gastroenterol 2011; 17: 5083-5088 [PMID: 22171142 DOI: 10.3748/wjg.v17.i46.5083]
61. Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg 1987; 206: 30-39 [PMID: 3038039]
62. Berry K, Ioannou GN. Are patients with Child's A cirrhosis and hepatocellular carcinoma appropriate candidates for liver transplantation? Am J Transplant 2012; 12: 706-717 [PMID: 22123435 DOI: 10.1111/j.1600-6143.2011.03853.x]
63. Eroʇlu A, Demirci S, Akbulut H, Sever N, Demirer S, Unal AE. Effect of granulocyte-macrophage colony-stimulating factor on hepatic regeneration after 70% hepatectomy in normal and cirrhotic rats. HPB (Oxford) 2002; 4: 67-73 [PMID: 18332927 DOI: 10.1080/136518202760378425]
64. Kaido T, Yoshikawa A, Seto S, Yamaoka S, Furuyama H, Arii S, Takahashi Y, Imamura M. Pretreatment with soluble thrombomodulin prevents intrasinusoidal coagulation and liver dysfunction following extensive hepatectomy in cirrhotic rats. Thromb Haemost 1999; 82: 1302-1306 [PMID: 10544918]
65. Yang ZF, Lau CK, Ngai P, Lam SP, Ho DW, Poon RT, Fan ST. Cardiotrophin-1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation. Liver Int 2008; 28: 622-631 [PMID: 18312290 DOI: 10.1111/j.1478-3231.2008.01687.x]
66. Luo SM, Liang LJ, Lai JM. Effects of recombinant human growth hormone on remnant liver after hepatectomy in hepatocellular carcinoma with cirrhosis. World J Gastroenterol 2004; 10: 1292-1296 [PMID: 15112344]
67. Bahde R, Kebschull L, Stöppeler S, Zibert A, Siaj R, Hölzen JP, Minin E, Schmidt HH, Spiegel HU, Palmes D. Role of angiotensin-1 receptor blockade in cirrhotic liver resection. Liver Int 2011; 31: 642-655 [PMID: 21457437 DOI: 10.1111/j.1478-3231.2011.02493.x]
68. Spira G, Mawasi N, Paizi M, Anbinder N, Genina O, Alexiev R, Pines M. Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats. J Hepatol 2002; 37: 331-339 [PMID: 12175628]
69. Iozzo RV, San Antonio JD. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J Clin Invest 2001; 108: 349-355 [PMID: 11489925]
70. Goldshmidt O, Yeikilis R, Mawasi N, Paizi M, Gan N, Ilan N, Pappo O, Vlodavsky I, Spira G. Heparanase expression during normal liver development and following partial hepatectomy. J Pathol 2004; 203: 594-602 [PMID: 15095483 DOI: 10.1002/path.1554]
71. Carmel J, Arish A, Shoshany G, Baruch Y. Heparanase accelerates the proliferation of both hepatocytes and endothelial cells early after partial hepatectomy. Exp Mol Pathol 2012; 92: 202-209 [PMID: 22305926 DOI: 10.1016/j.yexmp.2012.01.002]
72. Ohayon O, Mawasi N, Pevzner A, Tryvitz A, Gildor T, Pines M, Rojkind M, Paizi M, Spira G. Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats. Lab Invest 2008; 88: 627-633 [PMID: 18458672 DOI: 10.1038/labinvest.2008.30]
73. Gnainsky Y, Spira G, Paizi M, Bruck R, Nagler A, Genina O, Taub R, Halevy O, Pines M. Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL-1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone. Cell Tissue Res 2006; 324: 385-394 [PMID: 16508789 DOI: 10.1007/s00441-005-0092-1]
74. Peng Y, Du K, Ramirez S, Diamond RH, Taub R. Mitogenic up-regulation of the PRL-1 protein-tyrosine phosphatase gene by Egr-1. Egr-1 activation is an early event in liver regeneration. J Biol Chem 1999; 274: 4513-4520 [PMID: 9988683]
75. Mueller L, Broering DC, Meyer J, Vashist Y, Goettsche J, Wilms C, Rogiers X. The induction of the immediate-earlygenes Egr-1, PAI-1 and PRL-1 during liver regeneration in surgical models is related to increased portal flow. J Hepatol 2002; 37: 606-612 [PMID: 12399226]
76. Werner SR, Lee PA, DeCamp MW, Crowell DN, Randall SK, Crowell PL. Enhanced cell cycle progression and down regulation of p21(Cip1/Waf1) by PRL tyrosine phosphatases. Cancer Lett 2003; 202: 201-211 [PMID: 14643450]
77. Wang J, Kirby CE, Herbst R. The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis. J Biol Chem 2002; 277: 46659-46668 [PMID: 12235145 DOI: 10.1074/jbc.M206407200]
78. Nissen NN, Martin P. Hepatocellular carcinoma: the highrisk patient. J Clin Gastroenterol 2002; 35: S79-S85 [PMID: 12394210]
79. Wu SD, Ma YS, Fang Y, Liu LL, Fu D, Shen XZ. Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treat Rev 2012; 38: 218-225 [PMID: 21763074 DOI: 10.1016/j.ctrv.2011.06.010]
80. Okita K, Sakaida I, Hino K. Current strategies for chemoprevention of hepatocellular carcinoma. Oncology 2002; 62 Suppl 1: 24-28 [PMID: 11868781]
81. Okuda K. Hepatocellular carcinoma. J Hepatol 2000; 32: 225-237 [PMID: 10728807]
82. Menke A, Adler G. TGFbeta-induced fibrogenesis of the pancreas. Int J Gastrointest Cancer 2002; 31: 41-46 [PMID: 12622414]
83. Go VL, Gukovskaya A, Pandol SJ. Alcohol and pancreatic cancer. Alcohol 2005; 35: 205-211 [PMID: 16054982]
84. Maisonneuve P, Lowenfels AB. Chronic pancreatitis and pancreatic cancer. Dig Dis 2002; 20: 32-37 [PMID: 12145418 DOI: 10.1159/000063165]
85. Nagler A, Ohana M, Shibolet O, Shapira MY, Alper R, Vlodavsky I, Pines M, Ilan Y. Suppression of hepatocellular carcinoma growth in mice by the alkaloid coccidiostat halofuginone. Eur J Cancer 2004; 40: 1397-1403 [PMID: 15177499]
86. Taras D, Blanc JF, Rullier A, Dugot-Senant N, Laurendeau I, Bièche I, Pines M, Rosenbaum J. Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition. Neoplasia 2006; 8: 312-318 [PMID: 16756723]
87. Spector I, Honig H, Kawada N, Nagler A, Genin O, Pines M. Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development. Pancreas 2010; 39: 1008-1015 [PMID: 20442678 DOI: 10.1097/MPA.0b013e3181da8aa3]
88. Spector I, Zilberstein Y, Lavy A, Nagler A, Genin O, Pines M. Involvement of host stroma cells and tissue fibrosis in pancreatic tumor development in transgenic mice. PLoS One 2012; 7: e41833 [PMID: 22848627 DOI: 10.1371/journal.pone.0041833]
89. Abramovitch R, Dafni H, Neeman M, Nagler A, Pines M. Inhibition of neovascularization and tumor growth, and facilitation of wound repair, by halofuginone, an inhibitor of collagen type I synthesis. Neoplasia 1999; 1: 321-329 [PMID: 10935487]
90. Gavish Z, Pinthus JH, Barak V, Ramon J, Nagler A, Eshhar Z, Pines M. Growth inhibition of prostate cancer xenografts by halofuginone. Prostate 2002; 51: 73-83 [PMID: 11948962 DOI: 10.1002/pros.10059]
91. Gross DJ, Reibstein I, Weiss L, Slavin S, Dafni H, Neeman M, Pines M, Nagler A. Treatment with halofuginone results in marked growth inhibition of a von Hippel-Lindau pheochromocytoma in vivo. Clin Cancer Res 2003; 9: 3788-3793 [PMID: 14506172]
92. Pinthus JH, Sheffer Y, Nagler A, Fridman E, Mor Y, Genina O, Pines M. Inhibition of Wilms tumor xenograft progression by halofuginone is accompanied by activation of WT-1 gene expression. J Urol 2005; 174: 1527-1531 [PMID: 16148645]
93. Sheffer Y, Leon O, Pinthus JH, Nagler A, Mor Y, Genin O, Iluz M, Kawada N, Yoshizato K, Pines M. Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect. Mol Cancer Ther 2007; 6: 570-577 [PMID: 17267660 DOI: 10.1158/1535-7163.MCT-06-0468]
94. Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am J Physiol Gastrointest Liver Physiol 2011; 300: G723-G728 [PMID: 21292997 DOI: 10.1152/ajpgi.00414.2010]