Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: An overview

Journal of Translational Medicine

Volumn 9, Issue 1, 2011, Pages

  Marra, Monica ^a   Sordelli, Ignazio M ^a   Lombardi, Angela ^a   Lamberti, Monica ^a   Tarantino, Luciano ^b   Giudice, Aldo ^c   Stiuso, Paola ^a   Abbruzzese, Alberto ^a   Sperlongano, Rossella ^a   Accardo, Marina ^d   Agresti, Massimo ^a   Caraglia, Michele ^a   Sperlongano, Pasquale ^a  

^a SECOND UNIVERSITY OF NAPLES   (Italy)

^b SAN GIOVANNI DI DIO HOSPITAL   (Italy)

^c NATIONAL CANCER INSTITUTE   (Italy)

^d UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

AROMATIC HYDROCARBON RECEPTOR; B RAF KINASE; BETA CATENIN; BEVACIZUMAB; BIOLOGICAL MARKER; BRIVANIB; CATALASE; CEDIRANIB; CETUXIMAB; ERLOTINIB; EVEROLIMUS; FRIZZLED PROTEIN; GEFITINIB; GEMCITABINE; GLUTATHIONE PEROXIDASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LAPATINIB; MANGANESE SUPEROXIDE DISMUTASE; MITOGEN ACTIVATED PROTEIN KINASE; NITRIC OXIDE; OCTREOTIDE; PLACEBO; RAS PROTEIN; REACTIVE OXYGEN METABOLITE; SORAFENIB; SUNITINIB; SUPEROXIDE DISMUTASE; THALIDOMIDE; WNT3 PROTEIN; TUMOR MARKER;

ADVANCED CANCER; CANCER COMBINATION CHEMOTHERAPY; DNA DAMAGE; DOWN REGULATION; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG TOLERABILITY; HEPATITIS B VIRUS; HEPATITIS C VIRUS; HUMAN; LIPID PEROXIDATION; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; METASTASIS POTENTIAL; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; OXIDATIVE STRESS; PROGRESSION FREE SURVIVAL; REVIEW; SIGNAL TRANSDUCTION; TREATMENT DURATION; UNSPECIFIED SIDE EFFECT; LIVER TUMOR; METABOLISM; PATHOLOGY;

CARCINOMA, HEPATOCELLULAR; HUMANS; LIVER NEOPLASMS; OXIDATIVE STRESS; TUMOR MARKERS, BIOLOGICAL;

EID: 80053608796     PISSN: None     EISSN: 14795876     Source Type: Journal    
DOI: 10.1186/1479-5876-9-171     Document Type: Review

References (157)

1. McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF. International trends and patterns of primary liver cancer. Int J Cancer 2001, 94:290-6.
2. Bosch FX, Ribes J, Díaz M, Cléries R. Primary Liver Cancer: Worldwide Incidence and Trends. Gastroenterology 2004, 127:S5-S16.
3. Larson AM. The Epidemiology of Hepatocellular Carcinoma in HCV. Curr Hepat Reps 2005, 4:145-152.
4. Levi F, Lucchini F, Negri E, La Vecchia C. Continuing declines in cancer mortality in the European Union. Ann Oncol 2007, 18:593-595.
5. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci 2002, 963:13-20.
6. La Vecchia C, Negri E, Pilucchi C. The rise and fall in primary liver cancer mortality in Italy. Dig Liver Dis 2002, 34:169-171.
7. Okuda K. Hepatocellular carcinoma: recent progress. Hepatology 1992, 15:948-63.
8. Liu JH, Chen PW, Asch SM, Busuttil RW, Ko CY. Surgery for hepatocellular carcinoma: does it improve survival?. Ann Surg Oncol 2004, 11:298-303.
9. Bosch FX, Ribes J, Borràs J. Epidemology of primary liver cancer. Semin Liver Dis 1999, 193:271-85.
10. Yang JC, Teng CF, Wu HC, Tsai HW, Chuang HC, Tsai TF, Hsu YH, Huang W, Wu LW, Su IJ. Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis. Hepatology 2009, 496:1962-71.
11. Iavarone M, Lampertico P, Iannuzzi F, Manenti E, Donato MF, Arosio E, Bertolini F, Primignani M, Sangiovanni A, Colombo M. Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma. J Viral Hepat 2007, 142:133-9.
12. De Giorgi V, Monaco A, Worchech A, Tornesello M, Izzo F, Buonaguro L, Marincola FM, Wang E, Buonaguro FM. Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma. J Transl Med 2009, 12(7):85.
13. Besaratinia A, Kim SI, Hainaut P, Pfeifer GP. In vitro recapitulating of TP53 mutagenesis in hepatocellular carcinoma associated with dietary aflatoxin B1 exposure. Gastroenterology 2009, 1373:1127-37.
14. Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology 2004, 127:S72-8.
15. Franceschi S, Montella M, Polesel J, La Vecchia C, Crispo A, Dal Maso L, Casarin P, Izzo F, Tommasi LG, Chemin I, Trépo C, Crovatto M, Salamini R. Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy. Cancer Epidemiol Biomarkers Prev 2006, 154:683-9.
16. Adkins RH. Clinical significance of concomitant hepatitis C infection in patients with alcoholic liver disease. Hepatology 1994, 19:554-557.
17. Ming L, Thorgeirsson SS, Gail MH, Lu P, Harris CC, Wang N, Shao Y, Wu Z, Liu G, Wang X, Sun Z. Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology 2002, 36:1214-1220.
18. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002, 36:1206-1213.
19. Ohata K, Hamasaki K, Toriyama K, Matsumoto K, Saeki A, Yanagi K, Abiru S, Nakagawa Y, Shigeno M, Miyazoe S, Ichikawa T, Ishikawa H, Nakao K, Educhi K. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 2003, 97:3036-3043.
20. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol 2001, 96:2462-2467.
21. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 2005, 54:533-539.
22. Chokshi MM, Marrero JA. Hepatocellular carcinoma. Curr Opin Gastroenterol 2001, 17:276-280.
23. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000, 100:57-70.
24. Theise ND, Park YN, Kojiro M. Dysplastic nodules and hepatocarcinogenesis. Clin Liver Dis 2002, 6:497-512.
25. Borzio M, Fargion S, Borzio F, Fracanzani AL, Croce AM, Stroffolini T, Oldani S, Cotichini R, Roncalli M. Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development. J Hepatol 2003, 39:208-214.
26. Branda M, Wands JR. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology 2006, 43:891-902.
27. Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis 2003, 23:385-396.
28. Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Purcell RH, Alter HJ. Interrelationship of bloodtransfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis bydetection of antibody to hepatitis C virus. Hepatology 1990, 12:671-675.
29. McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis 2005, 25:S3-S8.
30. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000, 64(1):51-68.
31. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002, 31:339-346.
32. Feitelson MA. Hepatitis B virus in hepatocarcinogenesis. J Cell Physiol 1999, 181(2):188-202.
33. Yuen MF, Wu PC, Lai VC, Lau JY, Lai CL. Expression of c-Myc, c-Fos, and c-jun in hepatocellular carcinoma. Cancer 2001, 911:106-12.
34. Chirillo P, Pagano S, Natoli G, Puri PL, Burgio VL, Balsano C, Levrero M. The hepatitis B virus X gene induces p53-mediated programmed cell death. Proc Natl Acad Sci USA 1997, 94:8162-8167.
35. Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Brechot C. Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogene 1999, 18:4848-4859.
36. Hu Z, Zhang Z, Doo E, Coux O, Goldberg AL, Liang TJ. Hepatitis B virus × protein is both a substrate and a potential inhibitor of the proteasome complex. J Virol 1999, 73:7231-7240.
37. Xu Z, Jensen G, Yen TS. Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum. J Virol 1997, 71:7387-7392.
38. Baozong L, Bo G, Linbai Y, Xue H, Wei W, Lingbao K, Xiaonan F, Yingchun Z, Hong Z, Shanshan L, Zhenghui W, Li Y. Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response. Virus Research 2007, 124:44-49.
39. Tellinghuisen, Rice. Interaction between hepatitis C virus proteins and host cell factors. Curr Opin Microbiol 2002, 5(4):419-27.
40. Westaway EG, Mackenzie JM, Kenney MT, Jones MK, Khromykh AA. Ultrastructure of Kunjin virusinfected cells: colocalization of NS1 and NS3 with doublestranded RNA, and of NS2B with NS3, in virus-induced membrane structures. J Virol 1997, 71:6650-6661.
41. Weiland F, Eiland E, Nger G, Sallmuller A, Thiel H. Localization of pestivrial envelope proteins Erns and E2 at the cell surface and on isolated particles. J Gen Virol 1999, 80:1157-1165.
42. Bartenschlager R, Lohmann V. Replication of hepatitis C virus. J Gen Virol 2000, 81:1631-1648.
43. Parkin DM, Bray F, Ferlay J, Pisani P. Estimatine the world cancer burden: Globocan 2000. Int J Cancer 2001, 94:153-156.
44. Giambartolomei S, Covone F, Levrero M, Balsano C. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus HCV core protein. Oncogene 2001, 20:2606-2610.
45. Ray RB, Steele R, Meyer K, Ray R. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem 1997, 272:10983-10986.
46. Lu W, Lo SY, Chen M, Wu K, Fung YK, Ou JH. Activation of p53 tumor suppressor by hepatitis C virus core protein. Virology 1999, 264:134-141.
47. Alisi A, Giambartolomei S, Cupelli F, Merlo P, Fontemaggi G, Spaziani A. Physical and functional interaction between HCV core protein and the different p73 isoforms. Oncogene 2003, 22:2573-2580.
48. Cho J, Baek W, Yang S, Chang J, Sung YC, Suh M. HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation. Biochim Biophys Acta 2001, 1538:59-66.
49. Wang F, Yoshida I, Takamatsu M, Ishido S, Fujita T, Oka K. Complex formation between hepatitis C virus core protein and p21Waf1/Cip1/Sdi1. Biochem Biophys Res Commun 2000, 273:479-484.
50. Varaklioti A, Vassilaki N, Georgopoulou U, Mavromara P. Alternate translation occurs within the core coding region of the hepatitis C viral genome. J Biol Chem 2002, 277:17713-17721.
51. Yamanaka T, Uchida M, Doi T. Innate form of HCV core protein plays an important role in the localization and the function of HCV core protein. Biochem Biophys Res Commun 2002, 294:521-527.
52. Capitanio N, Moradpour D, Piccoli C. Hepatitis C virus proteins promote mitochondrial bioenergetic dysfunction and nitro-oxidative stress: insights into pathogenesis. Drug Discovery Today: Disease Mechanisms 2009, 6:e3-e10.
53. Jordan R, Wang L, Graczyk TM, Block TM, Romano PR. Replication of a cytopathic strain of bovine viral diarrhea virus activates PERK and induces endoplasmic reticulum stress-mediated apoptosis of MDBK cells. J Virol 2002, 76:9588-9599.
54. Tardif KD, Mori K, Siddiqui A. Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 2002, 76:7453-7459.
55. Waris G, Tardif KD, Siddiqui A. Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. Biochem Pharmacol 2002, 64:1425-1430.
56. Ferber MJ, Montoya DP, Yu C, Aderca I, McGee A, Thorland EC, Nagorney DM, Gostout BS, Burgart LJ, Boix L, Bruix J, Mcmahon BJ, Cheung TH, Chung T, Wong YM, Smith DI, Roberts LR. Integrations of the hepatitis B virus HBV and human papillomavirus HPV into the human telomerase reverse transcriptase hTERT gene in liver and cervical cancers. Oncogene 2003, 22:3813-3820.
57. Farazi PA, De Pinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006, 6:674-687.
58. Taniguchi H, Kato N, Otsuka M, Goto T, Yoshida H, Stiratori Y, Omata M. Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. J Med Virol 2004, 72:52-59.
59. Lee JS, Thorgeirsson SS. Comparative and integrative functional genomics of HCC. Oncogene 2006, 25:3801-3809.
60. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008, 484:1312-1327.
61. Edamoto Y, Hara A, Biernat W, Terracciano L, Cathomas G, Riehle HM, Matsuda M, Fujii H, Scoazec JY, Ohgaki H. Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. Int J Cancer 2003, 106:334-341.
62. Liu YC, Chen CJ, Wu HS, Chan DC, Yu JC, Yang AH, Cheng YL, Lee SC, Harn HJ. Telomerase and c-myc expression in hepatocellular carcinomas. Eur J Surg Oncol 2004, 30:384-390.
63. Masaki T, Shiratori Y, Rengifo W, Igarashi K, Yamagata M, Kurokohchi K, Uchida N, Miyauchi Y, Yoshiji H, Watanabe S, Omata M, Kuriyama S. Cyclins and cyclin-dependent kinases: comparative study of hepatocellular carcinoma versus cirrhosis. Hepatology 2003, 37:534-543.
64. Calvisi DF, Conner EA, Ladu S, Lemmer ER, Factor VM, Thorgeirsson SS. Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer. J Hepatol 2005, 42:842-849.
65. Endo K, Ueda T, Ueyama J, Ohta T, Terada TT. Immunoreactive E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients' survival. Hum Pathol 2000, 31:558-565.
66. Inagawa S, Itabashi M, Adachi S, Kawamoto T, Hori M, Shimazaki J, Yoshimi F, Fukao K. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res 2002, 8:450-456.
67. Merle P, de la Monte S, Kim M, Herrmann M, Tanaka S, Bussche A, Von Dem Kew MC, Trepo C, Wands JR. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 2004, 127:1110-1122.
68. Merle P, Kim M, Herrmann M, Gupte A, Lefrancois L, Califano S, Trepo C, Tanaka S, Vitvitski L, de la Monte S, Wands JR. Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol 2005, 43:854-862.
69. Kim M, Lee HC, Tsedensodnom O, Hartley R, Lim YS, Yu E, Merle P, Wands JR. functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells. J Hepatol 2008, 485:780-91.
70. Lee TH, Tai DI, Cheng CJ, Sun CS, Lin CY, Sheu MJ, Lee WP, Peng CY, Wang AH, Tsai SL. Enhanced nuclear factor-kappa B-associated Wnt-1 expression in hepatitis B- and C-related hepatocarcinogenesis: identification by functional proteomics. J Biomed Sci 2006, 131:27-39.
71. Marshall C. How do small GTPase signal transduction pathways regulate cell cycle entry?. Curr Opin Cell Biol 1999, 11:732-736.
72. Hoscino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Constitutive activation of the 41/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 1999, 18:813-22.
73. Calvisi DF, Pinna F, Ladu S, Pellegrino R, Sanna V, Sini M, Daino L, Simile MM, De Miglio MR, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM. Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control. Int J Cancer 2008, 123:2057-2064.
74. Feo F, De Miglio MR, Simile MM, Muroni MR, Calvisi DF, Frau M, Pascale RM. Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim Biophys Acta 2006, 1765::126-147.
75. Pascale RM, Simile MM, De Miglio MR, Nufris A, Seddaiu MA, Muroni MR, Danni O, Rao KN, Feo F. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase activity and gene expression by dehydrocpiandrosterone in preneoplastic liver nodules. Carcinogenesis 1995, 16:1537-1542.
76. Newell P, Toffanin S, Villanueva A, Chiang DY, Minguez B, Cabellos L, Savic R, Hoshida Y, Lim KH, Melgar-Lesmes P, Yea S, Peix J, Deniz K, Fiel MI, Thung S, Alsinet C, Tovar V, Mazzaferro V, Bruix J, Roayaie S, Schwartz M, Friedman SL, Llovet JM. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J Hepatol 2009, 51:725-733.
77. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003, 3:11-22.
78. Hwang YH, Choi JY, Kim S, Chung ES, Kim T, Koh SS, Lee B, Bae SH, Kim J, Park YM. Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. Hepatol Res 2004, 29:113-121.
79. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol 2004, 41:864-880.
80. Lee JS, Grisham JW, Thorgeirsson SS. Comparative functional genomics for identifying models of human cancer. Carcinogenesis 2005, 266:1013-1020.
81. Okey AB. An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. Toxicol Sci 2007, 98:5-38.
82. Jesenberger V, Jentsch S. Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol 2002, 3:112-121.
83. Kim JW, Wang XW. Gene expression profiling of preneoplastic liver disease and liver cancer: a new era for improved early detection and treatment of these deadly diseases?. Carcinogenesis 2003, 24:363-369.
84. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000, 408:239-247.
85. Storz P. Reactive oxygen species in tumor progression. Front Biosci 2005, 10:1881-96.
86. Fruehauf JP, Meyskens FL. Reactive Oxygen Species: A Breath of Life or Death?. Clin Cancer Res 2007, 133:789-94.
87. Clemente C, Elba S, Buongiorno G, Guerra V, D'Attoma B, Orlando A, Russo F. Manganese superoxide dismutase activity and incidence of hepatocellular carcinoma in patients with Child-Pugh class A liver cirrhosis: a 7-year follow-up study. Liver Int 2007, 276:791-7.
88. Ridnour LA, Thomas DD, Switzer C, Flores-Santana W, Isenberg JS, Ambs S, Roberts DD, Wink DA. Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 2008, 19:73-76.
89. Prueitt RL, Boersma BJ, Howe TM, Goodman JE, Thomas DD, Ying L, Pfiester CM, Yfantis HG, Cottrell JR, Lee DH, Remaley AT, Hofseth LJ, Wink DA, Ambs S. Inflammation and IGF-I activate the Akt pathway in breast cancer. Int J Cancer 2007, 120:796-805.
90. Thomas DD, Espey MG, Ridnour LA, Hofseth LJ, Mancardi D, Harris CC, Wink DA. Hypoxic inducible factor 1alpha, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide. Proc Natl Acad Sci USA 2004, 101:8894-8899.
91. Pervin S, Singh R, Freije WA, Chaudhuri G. MKP-1-induced dephosphorylation of extracellular signal-regulated kinase is essential for triggering nitric oxide-induced apoptosis in human breast cancer cell lines: implications in breast cancer. Cancer Res 2003, 63:8853-8860.
92. Thomas DD, Ridnour LA, Espey MG, Donzelli S, Ambs S, Hussain SP, Harris CC, DeGraff W, Roberts DD, Mitchell JB, Wink DA. Superoxide fluxes limit nitric oxide-induced signalling. J Biol Chem 2006, 281:25984-25993.
93. Hausladen A, Stamler JS. Nitrosative stress. Methods Enzymol 1999, 300:389-95.
94. Bogdan C, Röllinghoff M, Diefenbach AM. The role of nitric oxide in innate immunity. Immunol Rev 2000, 173:17-26.
95. Kim YM, Son K, Hong SJ, Green A, Chen JJ, Tzeng E, Hierholzer C, Billiar TR. Inhibition of protein synthesis by nitric oxide correlates with cytostatic activity: nitric oxide induces phosphorylation of initiation factor eIF-2 alpha. Mol Med 1998, 4:179-190.
96. Bundy RE, Marczin N, Chester AH, Yacoub M. A redox-based mechanism for nitric oxide-induced inhibition of DNA synthesis in human vascular smooth muscle cells. Br. J Pharmacol 2000, 129:1513-1521.
97. Fujii J, Taniguchi N. Down regulation of superoxide dismutases and glutathione peroxidase by reactive oxygen and nitrogen species. Free Radic Res 1999, 31:301-308.
98. Berendji D, Kolb-Bachofen V, Meyer KL, Kröncke KD. Influence of nitric oxide on the intracellular reduced glutathione pool: different cellular capacities and strategies to encounter nitric oxide-mediated stress. Free Radic Biol Med 1999, 27:773-780.
99. Murphy MP. Nitric oxide and cell death. Biochim Biophys Acta 1999, 1411:401-414.
100. Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med 1991, 91:14S-22S.
101. Wink DA, Miranda KM, Espey MG, Pluta RM, Hewett SJ, Colton C, Vitek M, Feelisch M, Grisham MB. Mechanisms of the antioxidant effects of nitric oxide. Antioxid Redox Signal 2001, 3:203-13.
102. Kim YM, Bergonia H, Lancaster JR. Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett 1995, 374:228-32.
103. Chiu JJ, Wung BS, Hsieh HJ, Lo LW, Wang DL. Nitric oxide regulates shear stress-induced early growth response-1. Expression via the extracellular signal-regulated kinase pathway in endothelial cells. Circ Res 1999, 85:238-246.
104. Wulf D. Free Radicals in the Physiological Control of Cell Function. Physiol Rev 2002, 82:47-95.
105. Ma Y, Hendershot LM. The unfolding tale of the unfolded protein response. Cell 2001, 107(7):827-30.
106. Kaufman RJ. Stress signaling from the lumen of the endoplasmic retiuclum: coordination of gene transcriptional and translational controls. Genes Dev 1999, 13:1211-1233.
107. Wang X, McCullough KD, Franke TF, Holbrook NJ. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem 2000, 275:14624-14631.
108. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003, 22:5093-5107.
109. Sumida Y, Nakashima T, Yoh T, Nakjima Y, Ishikawa H, Mitsuyoshi H, Sakamoto Y, Okanoue T, Kashima K, Nakamura H, Yodoi J. Serum thioredoxin levels as an indicator of oxidative stress in patients with hepatitis C virus infection. J Hepatology 2000, 33:616-622.
110. Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, Kasai H. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res 1994, 54:3171-3172.
111. Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T, Imai K, Todoroki T, Kimura S, Koike K. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001, 61:4365-4370.
112. Altimari A, Fiorentino M, Gabusi E, Gruppioni E, Corti B, D'Errico A, Grigioni WF. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primari liver tumours. Dig Liver Dis 2003, 35:332-338.
113. Forner A, Hessheimer AJ, Isabel Real M, Bruix J. Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol 2006, 602:89-98.
114. Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, Yeung C, Wong J. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg 1999, 229:322-30.
115. Ota K, Teraoka S, Kawai T. Donor difficulties in Japan and Asian countries. Transplant Proc 1995, 27:83-6.
116. Palmer DH, Hussain SA, Johnson PJ. Systemic therapies for hepatocellular carcinoma. Expert Opin Invest Drugs 2004, 13:1555-68.
117. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999, 82:241-250.
118. Gibbs JB. Anticancer drug targets: Growth factors and growth factor signaling. J Clin Invest 2000, 105:9-13.
119. Kaneko Y, Shibuya M, Nakayama T, Hayashida N, Toda G, Endo Y, Oka H, Oda T. Hypomethylation of c-myc and epidermal growth factor receptor genes in human hepatocellular carcinoma and fetal liver. Jpn J Cancer Res 1985, 76:1136-1140.
120. Xu YH, Jiang WL, Peng SF. EGFR/HER1 expression and EGF stimulation of proliferation in human liver carcinoma cells. Shi Yan Sheng Wu Xue Bao 1989, 22:445-453.
121. Philip AP, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C. Study of Erlotinib OSI-774 in Patients With Advanced Hepatocellular Cancer. J Clin Oncol 2005, 23:6657-6663.
122. Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T, Rashid A, Dancey J, Abbruzzese JL. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007, 1105:1059-67.
123. Zhu AX, Stuart K, Blaszkowsky LS, Muzikansky A, Reitberg DP, Clark JW, Enzinger PC, Bhargava P, Meyerhardt JA, Horgan K, Fuchs CS, Ryan DP. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007, 1103:581-9.
124. Asnacios A, Fartoux L, Romano O, Tesmoingt C, Louafi SS, Mansoubakht T, Artru P, Poynard T, Rosmorduc O, Hebbar M, Taieb J. Gemcitabine plus oxaliplatin GEMOX combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study. Cancer 2008, 11212:2733-2739.
125. Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, Chen H, Clark-Garvey S, Weinberg A, Mandeli J, Christos P, Mazumdar M, Popa E, Brown RS, Rafii S, Schwartz JD. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008, 26:2992-8.
126. Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, Kaseb A, Glover K, Davila M, Abbruzzese J. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 2009, 276:843-50.
127. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003, 9:327-37.
128. Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, Zappa M, Lanzalone S, Lin X, Deprimo S, Harmon C, Ruiz-Garcia A, Lechuga MJ, Cheng AL. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol 2009, 108:794-800.
129. Nathan CF, Cohn ZA. Antitumor effects of hydrogen peroxide in vivo. J Exp Med 1981, 1545:1539-53.
130. Simizu Takada M, Umezawa K, Imoto M. Requirement of caspase-3-like protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs. J Biol Chem 1998, 273:26900-26907.
131. Yoshikawa T, Kokura S, Tainaka K, Naito Y, Kondo M. A novel cancer therapy based on oxygen radicals. Cancer Res 1995, 55:1617-1620.
132. Chaparro M, González Moreno L, Trapero-Marugán M, Medina J, Moreno-Otero R. Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents. Aliment Pharmacol Ther 2008, 2811-12:1269-77.
133. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006, 66:11851-11858.
134. Abou-Alfa GK. Hepatocellular carcinoma:molecular biology and therapy. Semin Oncol 2006, 66:11851-858.
135. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard J-Y, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006, 24:4293-300.
136. Yau T, Chan P, Epstein R, Poon RT. Management ofadvanced hepatocellular carcinoma in the era of targeted therapy. Liver Int 2009, 291:10-7.
137. Llovet JM, Di Bisceglie A, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ. Design and end-points of clinical trials in HCC. J Natl Cancer Inst 2008, 100:698-711.
138. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996, 334:246-254.
139. Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial. World J Gastroenterol 2007, 1323:3164-3170.
140. Attia S, Holen KD, Thomas JP, Richie K, Dzelak T, Teeter K, Warren D, Bilger A, Fine J, Eickhoff J, Drinkwater N, Mulkerin D, Morgan-Meadows S. Biologic study of the effects of octreotide-LAR on growth hormone in unresectable and metastatic hepatocellular carcinoma. Clin Adv Hematol Oncol 2008, 61:44-54.
141. Samonakis DN, Notas G, Christodoulakis N, Kouroumalis EA. Mechanisms of action and resistance of somatostatin analogues for the treatment of hepatocellular carcinoma: a message not well taken. Dig Dis Sci 2008, 53:2359-65.
142. Montella L, Addeo R, Caraglia M, Faiola V, Guarrasi R, Vincenzi B, Palmeri A, Capasso E, Nocera V, Tarantino L, Ariete M, Martorelli A, Del Prete S. Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: A single center experience. Oncol Rep 2008, 20:385-90.
143. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J Natl Cancer Inst 2000, 92:205-16.
144. Del Prete S, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E, Palmieri G, Guarrasi R, Bianco M, Mamone R, Savastano C, Pisano A, Vincenzi B, Sabia A, D'Agostino A, Faiola V, Addeo R. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol 2009, 645:863-6.
145. Addeo R, Caraglia M, Del Prete S. Highlights of regional meeting of Italian Southern Oncological Group (GOIM): focus on hepatocellular carcinoma: biological and clinical background, therapeutic guide-lines and perspectives. 7 November 2008 Naples, Italy. Expert Opin Investig Drugs 2009, 18(3):373-8.
146. Corrocher R, Casaril M, Bellisola G, Gabrielli GB, Nicoli N, Guidi GC, De Sandre G. Severe impairment of antioxidant system in human hepatoma. Cancer 1986, 58:1658-1662.
147. Caraglia M, Giuberti G, Marra M, Addeo R, Montella L, Murolo M, Sperlongano P, Vincenzi B, Naviglio S, Del Prete S, Abbruzzese A, Stiuso P. Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR. Cell Death Dis 2011, 2:e150.
148. Casaril M, Corso F, Bassi A, Capra F, Gabrielli GB, Stanzial AM, Nicoli N, Corrocher R. Decreased activity of scavenger enzymes in human hepatocellular carcinoma, but not in liver metastases. Intl J Clin Lab Res 1994, 24:94-97.
149. Liaw KY, Lee PH, Wu FC, Tsai JS, Lin-Shiau SY. Zinc, copper, and superoxide dismutase in hepatocellular carcinoma. Am J Gastroenterol 1997, 9212:2260-2263.
150. Ngoka LCM. Dramatic down-regulation of oxidoreductases in human hepatocellular carcinoma hepG2 cells: proteomics and gene ontology unveiling new frontiers in cancer enzymology. Proteome Science 2008, 6:29.
151. Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003, 3:276-285.
152. De Maria N, Colantoni A, Fagiuoli S. Association between reactive oxygen species, disease activity in chronic hepatitis C. Free Radic Biol Med 1996, 21:291-295.
153. Coradini D, Speranza A. Histone deacetylase inhibitors for treatment of hepatocellular carcinoma. Acta Pharmacol Sin 2005, 26(9):1025-33.
154. Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M, Lauer UM, Bitzer M. HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 2006, 43(3):425-34.
155. Rubiolo JA, Mithieux G, Vega FV. Resveratrol protects primary rat hepatocytes against oxidative stress damage: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. Eur J Pharmacol 2008, 591:66-72.
156. Das S, Das DK. Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Target 2007, 6:168-73.
157. Bishayee A, Barnes KF, Bhatia D, Darvesh AS, Carroll RT. Resveratrol Suppresses Oxidative Stress and Inflammatory Response in Diethylnitrosamine-Initiated Rat Hepatocarcinogenesis. Cancer Prev Res (Phila) 2010, 3(6):753-63.