Potential for statins in the chemoprevention and management of hepatocellular carcinoma

Journal of Gastroenterology and Hepatology (Australia)

Volumn 27, Issue 11, 2012, Pages 1654-1664

  Lonardo, Amedeo ^a   Loria, Paola ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

Author keywords

Chemoprevention; Hepatocellular carcinoma; Management; Molecular pathogenesis; Portal hypertension; Statins

Indexed keywords

3 HYDROXY 3 METHYLGLUTARYL COENZYME A; ALANINE AMINOTRANSFERASE; ANTILIPEMIC AGENT; ARACHIDONIC ACID; ATORVASTATIN; C REACTIVE PROTEIN; CELECOXIB; CHOLESTEROL; COMPACTIN; ENZASTAURIN; FLUINDOSTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MEVINOLIN; MYC PROTEIN; PITAVASTATIN; PLACEBO; PRAVASTATIN; PROSTAGLANDIN; ROSUVASTATIN; SIMVASTATIN; STAT3 PROTEIN; TRIACYLGLYCEROL;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; ARTIFICIAL EMBOLISM; CANCER CELL; CANCER RISK; CANCER SURVIVAL; CARCINOGENESIS; CELL CYCLE ARREST; CELL DIFFERENTIATION; CELL GROWTH; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CHEMOPROPHYLAXIS; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL SYNTHESIS; CHROMOSOME ABERRATION; CHRONIC LIVER DISEASE; COFFEE; DRUG EFFECT; DRUG MEGADOSE; DRUG POTENTIATION; DRUG SAFETY; DRUG STRUCTURE; ENDOTHELIUM CELL; FOOD INTAKE; GASTROINTESTINAL HEMORRHAGE; HUMAN; HYPERCHOLESTEROLEMIA; IN VITRO STUDY; INFORMATION RETRIEVAL; KARYOTYPE; LIPOGENESIS; LIPOPHILICITY; LIVER CELL; LIVER CELL CARCINOMA; METABOLIC DISORDER; METASTASIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; ONCOGENE C MYC; PRIMARY PREVENTION; PRIORITY JOURNAL; REVIEW; SECONDARY PREVENTION; TARGET CELL; TRANSARTERIAL EMBOLIZATION;

CARCINOMA, HEPATOCELLULAR; GASTROINTESTINAL HEMORRHAGE; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERTENSION, PORTAL; LIVER NEOPLASMS;

EID: 84868119532     PISSN: 08159319     EISSN: 14401746     Source Type: Journal    
DOI: 10.1111/j.1440-1746.2012.07232.x     Document Type: Review

References (83)

1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132: 2557-2576.
2. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127 (5 Suppl. 1) S35-50.
3. Paradis V, Zalinski S, Chelbi E etal. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49: 851-859.
4. Bruix J, Llovet JM. Two decades of advances in hepatocellular carcinoma research. Semin. Liver Dis. 2010; 30: 1-2.
5. Borena W, Strohmaier S, Lukanova A etal. Metabolic risk factors and primary liver cancer in a prospective study of 578700 adults. Int. J. Cancer 2012; 131: 193-200.
6. Endo A. A historical perspective on the discovery of statins. Proc. Jpn. Acad. B Phys. Biol. Sci. 2010; 86: 484-493.
7. Steinberg D, Gotto AM Jr. Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside. JAMA 1999; 282: 2043-2050.
8. Tobert JA. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat. Rev. 2003; 2: 517-526.
9. Brown MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis. Science 1986; 232: 34-47.
10. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674.
11. Ding ZB, Shi YH, Zhou J etal. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 2008; 68: 9167-9175.
12. Naugler WE, Sakurai T, Kim S etal. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007; 317: 121-124.
13. Wong N, Lai P, Pang E, Leung TW, Lau JW, Johnson PJ. A comprehensive karyotypic study on human hepatocellular carcinoma by spectral karyotyping. Hepatology 2000; 32: 1060-1068.
14. Gauthaman K, Manasi N, Bongso A. Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells. Br. J. Pharmacol. 2009; 157: 962-973.
15. Gauthaman K, Fong CY, Bongso A. Statins, stem cells, and cancer. J. Cell. Biochem. 2009; 106: 975-983.
16. Zhao J, Zhao Y, Wang H, Gu X, Ji J, Gao C. Association between metabolic abnormalities and HBV related hepatocellular carcinoma in Chinese: a cross-sectional study. Nutr. J. 2011; 10: 49-57.
17. Kumada T, Toyoda H, Kiriyama S etal. Incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection who have normal alanine aminotransferase values. J. Med. Virol. 2010; 82: 539-545.
18. Morales A, Marí M, García-Ruiz C, Colell A, Fernández-Checa JC. Hepatocarcinogenesis and Ceramide/cholesterol metabolism. Anticancer Agents Med. Chem. 2012; 12: 364-375.
19. Abel S, De Kock M, van Schalkwyk DJ, Swanevelder S, Kew MC, Gelderblom WC. Altered lipid profile, oxidative status and hepatitis B virus interactions in human hepatocellular carcinoma. Prostaglandins Leukot. Essent. Fatty Acids 2009; 81: 391-399.
20. Montero J, Morales A, Llacuna L etal. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res. 2008; 68: 5246-5256.
21. Calvisi DF, Wang C, Ho C etal. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology 2011; 140: 1071-1083.
22. Cao Z, Fan-Minogue H, Bellovin DI etal. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res. 2011; 71: 2286-2297.
23. Falleti E, Fabris C, Toniutto P etal. Interleukin-6 polymorphisms and gender: relationship with the occurrence of hepatocellular carcinoma in patients with end-stage liver disease. Oncology 2009; 77: 304-313.
24. Liu Y, Fuchs J, Li C, Lin J. IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-induced STAT3 phosphorylation in human hepatocellular cancer cells. Cell Cycle. 2010; 9: 3423-3427.
25. Subramaniam PS, Torres BA, Johnson HM. So many ligands, so few transcription factors: a new paradigm for signaling through the STAT transcription factors. Cytokine 2001; 15: 175-187.
26. Nasimuzzaman M, Waris G, Mikolon D, Stupack DG, Siddiqui A. Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor. J. Virol. 2007; 81: 10249-10257.
27. Calliot F. Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence. World J. Gastroenterol. 2009; 15: 300-309.
28. Arnaud C, Burger F, Steffens S etal. Statins Reduce interleukin-6-induced C-reactive protein in human hepatocytes. New evidence for direct anti-inflammatory effects of statins. Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1231-1236.
29. Brantley EC, Benveniste EN. Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol. Cancer Res. 2008; 6: 675-684.
30. Costantino L, Barlocco D. STAT 3 as a target for cancer drug discovery. Curr. Med. Chem. 2008; 15: 834-843.
31. Loppnow H, Zhang L, Buerke M etal. Statins potently reduce the cytokine-mediated IL-6 release in SMC/MNC cocultures. J. Cell. Mol. Med. 2011; 15: 994-1004.
32. Jougasaki M, Ichiki T, Takenoshita Y, Setoguchi M. Statins suppress interleukin-6-induced monocyte chemo-attractant protein-1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells. Br. J. Pharmacol. 2010; 159: 1294-1303.
33. Kountouras J, Zavos C, Chatzopoulos D. Apoptosis in hepatocellular carcinoma. Hepatogastroenterology 2003; 50: 242-249.
34. Kountouras J, Zavos C, Chatzopoulos D. Apoptotic and anti-angiogenic strategies in liver and gastrointestinal malignancies. J. Surg. Oncol. 2005; 90: 249-259.
35. Spampanato C, De Maria S, Sarnataro M etal. Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. Int. J. Oncol. 2012; 40: 935-941.
36. Mukai M, Togawa A, Imamura F etal. Sustained tyrosine-phosphorylation of FAK through Rho-dependent adhesion to fibronectin is essential for cancer cell migration. Anticancer Res. 2002; 22 (6A): 3175-3184.
37. Sun B, Nishihira J, Yoshiki T etal. Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho-dependent pathway. Clin. Cancer Res. 2005; 11: 1050-1058.
38. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature 2002; 420: 629-635.
39. Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature 1993; 366: 643-654.
40. Wang W, Yang LY, Yang ZL, Huang GW, Lu WQ. Expression and significance of RhoC gene in hepatocellular carcinoma. World J. Gastroenterol. 2003; 9: 1950-1953.
41. Wang W, Yang LY, Huang GW etal. Genomic analysis reveals RhoC as a potential marker in hepatocellular carcinoma with poor prognosis. Br. J. Cancer 2004; 90: 2349-2355.
42. Wang W, Wu F, Fang F, Tao Y, Yang L. Inhibition of invasion and metastasis of hepatocellular carcinoma cells via targeting RhoC in vitro and in vivo. Clin. Cancer Res. 2008; 14: 6804-6812.
43. Bhuket TP, Higgins PD. Drug insight: statins and gastrointestinal cancer. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006; 3: 552-562.
44. Relja B, Meder F, Wang M etal. Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK. Int. J. Oncol. 2011; 38: 879-885.
45. Paragh G, Kertai P, Kovacs P, Paragh G Jr, Fülöp P, Foris G. HMG CoA reductase inhibitor fluvastatin arrests the development of implanted hepatocarcinoma in rats. Anticancer Res. 2003; 23 (5A): 3949-3954.
46. Paragh G, Fóris G, Paragh G Jr etal. Different anticancer effects of fluvastatin on primary hepatocellular tumors and metastases in rats. Cancer Lett. 2005; 222: 17-22.
47. Sutter AP, Maaser K, Höpfner M, Huether A, Schuppan D, Scherübl H. Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor. J. Hepatol. 2005; 43: 808-816.
48. Kim W, Yoon JH, Kim JR etal. Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma. Cancer Chemother. Pharmacol. 2009; 64: 497-507.
49. Björkhem-Bergman L, Acimovic J, Torndal UB, Parini P, Eriksson LC. Lovastatin prevents carcinogenesis in a rat model for liver cancer. Effects of ubiquinone supplementation. Anticancer Res. 2010; 30: 1105-1112.
50. Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 2010; 70: 7699-7709.
51. Gao J, Jia WD, Li JS etal. Combined inhibitory effects of celecoxib and fluvastatin on the growth of human hepatocellular carcinoma xenografts in nude mice. J. Int. Med. Res. 2010; 38: 1413-1427.
52. Shimizu M, Yasuda Y, Sakai H etal. Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 2011; 11: 281-291.
53. Tijeras-Raballand A, Hainaud-Hakim P, Contreres JO etal. Rosuvastatin counteracts vessel arterialisation and sinusoid capillarisation, reduces tumour growth, and prolongs survival in murine hepatocellular carcinoma. Gastroenterol. Res. Pract. 2010; 2010: 640797.
54. Polo MP, Crespo R, de Bravo MG. Geraniol and simvastatin show a synergistic effect on a human hepatocarcinoma cell line. Cell Biochem. Funct. 2011; 29: 452-458.
55. Argo CK, Loria P, Caldwell SH, Lonardo A. Statins in liver disease: a molehill, an iceberg, or neither? Hepatology 2008; 48: 662-669.
56. Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 2011; 54: 463-471.
57. Ertle J, Dechêne A, Sowa JP etal. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 2011; 128: 2436-2443.
58. Musso G, Cassader M, Gambino R. Cholesterol-lowering therapy for the treatment of nonalcoholic fatty liver disease: an update. Curr. Opin. Lipidol. 2011; 22: 489-496.
59. Kawata S, Yamasaki E, Nagase T etal. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br. J. Cancer 2001; 84: 886-891.
60. Friis S, Poulsen AH, Johnsen SP etal. Cancer risk among statin users: a population-based cohort study. Int. J. Cancer 2005; 114: 643-647.
61. El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009; 136: 1601-1608.
62. Chiu HF, Ho SC, Chen CC, Yang CY. Statin use and the risk of liver cancer: a population-based case-control study. Am. J. Gastroenterol. 2011; 106: 894-898.
63. Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J. Clin. Oncol. 2012; 30: 623-630.
64. Koh WP, Robien K, Wang R, Govindarajan S, Yuan JM, Yu MC. Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study. Br. J. Cancer 2011; 105: 1430-1435.
65. Reid FD, Cook DG, Whincup PH. Use of statins in the secondary prevention of coronary heart disease: is treatment equitable? Heart 2002; 88: 15-19.
66. Butt MS, Sultan MT. Coffee and its consumption: benefits and risks. Crit. Rev. Food Sci. Nutr. 2011; 51: 363-373.
67. El-Serag HB. Hepatocellular carcinoma. N. Engl. J. Med. 2011; 365: 1118-1127.
68. Mancini GB, Baker S, Bergeron J etal. Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference. Can. J. Cardiol. 2011; 27: 635-662.
69. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127 (Suppl. 1): S35-S50.
70. Chen CJ, Yang HI, Su J etal. REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65-73.
71. Cholesterol Treatment Trialists' (CTT). Collaboration lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175000 people in 27 randomised trials of statin therapy. PLoS ONE 2012; 7: 1-10.
72. Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K. The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 1984; 54: 1461-1465.
73. Ripoll C, Groszmann RJ, Garcia-Tsao G etal. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J. Hepatol. 2009; 50: 923-928.
74. Notas G, Xidakis C, Valatas V, Kouroumalis A, Kouroumalis E. Levels of circulating endothelin-1 and nitrates/nitrites in patients with virus-related hepatocellular carcinoma. J. Viral Hepat. 2001; 8: 63-69.
75. Bosch J, Abraldes JG, Fernández M, García-Pagán JC. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J. Hepatol. 2010; 53: 558-567.
76. Abraldes JG, La Mura V, Bosch J. Statins in portal hypertension. In: Portal Hypertension V, 2011: Wiley Online Library Portal Hypertension V: Proceedings of the Fifth Baveno International Consensus Workshop, Fifth Edition Edited by Roberto de Franchis 2011 Blackwell Publishing Ltd. 2011. ISBN: 978-1-444-33449-4.
77. Dell'Era A, Sotela JC, Fabris FM etal. Primary prophylaxis of variceal bleeding in cirrhotic patients: a cohort study. Dig. Liver Dis. 2008; 40: 936-943.
78. Abraldes JG, Albillos A, Bañares R etal. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136: 1651-1658.
79. Zafra C, Abraldes JG, Turnes J etal. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004; 126: 749-755.
80. Abraldes JG, Rodríguez-Vilarrupla A, Graupera M etal. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J. Hepatol. 2007; 46: 1040-1046.
81. Gracia-Sancho J, Russo L, García-Calderó H, García-Pagán JC, García-Cardeña G, Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut 2011; 60: 517-524.
82. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR etal. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46: 1453-1463.
83. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010; 340: c2197.