Advertisement

Current Oncology Reports

, Volume 4, Issue 6, pp 464–470 | Cite as

Prevention of liver cancer

  • Kathryn Z. Guyton
  • Thomas W. Kensler
Article

Abstract

Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide. Prominent risk factors for HCC include viral hepatitis infection; dietary exposure to hepatotoxic contaminants such as aflatoxins; alcoholism; smoking; and male gender. This review highlights ongoing efforts in HCC prevention. Strategies include vaccination against, and treatment of, viral hepatitis infection. In addition to interferon α, an acyclic retinoid (all-trans-3,7,11, 15-tetramethyl-2,4,6,10,14-hexadecapentanoic acid), glycyrrhizin and ginseng are currently under clinical investigation for HCC prevention in Japanese hepatitis C patients. Several recent clinical studies in a Chinese region of pervasive aflatoxin contamination also support the approach of favorably altering aflatoxin metabolism and excretion using the chemopreventive agents oltipraz or chlorophyllin. Agents exhibiting chemopreventive efficacy in preclinical HCC models include vitamins A, D, and E, herbal extracts, a 5α-reductase inhibitor, green tea, and D-limonene. Efforts to elucidate the molecular lesions and processes underlying HCC development have identified several putative molecular targets for preventive interventions. These include genes and gene products controlling viral replication, carcinogen metabolism, signal transduction, cell-cycle arrest, apoptosis, proliferation, and oxidative stress.

Keywords

Aflatoxin Glycyrrhizin Ebselen Oltipraz Acyclic Retinoid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Teo EK, Fock KM: Hepatocellular carcinoma: an Asian perspective. Dig Dis 2001, 19:263–268.PubMedCrossRefGoogle Scholar
  2. 2.
    Koda M, Murawaki Y, Mitsuda A, et al.: Predictive factors for intrahepatic recurrence after percutaneous ethanol injection therapy for small hepatocellular carcinoma. Cancer 2000, 88:529–537.PubMedCrossRefGoogle Scholar
  3. 3.
    Bilimoria MM, Lauwers GY, Doherty DA, et al.: Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg 2001, 136:528–535.PubMedCrossRefGoogle Scholar
  4. 4.
    Evans AA, Chen G, Ross EA, et al.: Eight-year follow-up of the 90,000-person Haimen City cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer Epidemiol Biomarkers Prev 2002, 11:369–376. This prospective cohort study of 58,545 men and 25,340 women identified HBV infection as the primary risk factor for HCC mortality in this Haimen City, China cohort.PubMedGoogle Scholar
  5. 5.
    Yoshizawa H: Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future. Oncology 2002, 62(suppl 1):8–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Mori M, Hara M, Wada I, et al.: Prospective study of hepatitis B and C viral infections, cigarette smoking, alcohol consumption, and other factors associated with hepatocellular carcinoma risk in Japan. Am J Epidemiol 2000, 151:131–139.PubMedGoogle Scholar
  7. 7.
    Hellerbrand C, Hartmann A, Richter G, et al.: Hepatocellular carcinoma in southern Germany: epidemiological and clinicopathological characteristics and risk factors. Dig Dis 2001, 19:345–351.PubMedCrossRefGoogle Scholar
  8. 8.
    Monto A, Wright TL: The epidemiology and prevention of hepatocellular carcinoma. Semin Oncol 2001, 28:441–449.PubMedCrossRefGoogle Scholar
  9. 9.
    Kao JH, Chen DS: Recent updates in hepatitis vaccination and the prevention of hepatocellular carcinoma. Int J Cancer 2002, 97:269–271.PubMedCrossRefGoogle Scholar
  10. 10.
    Prince AM, Shata MT: Immunoprophylaxis of hepatitis C virus infection. Clin Liver Dis 2001, 5:1091–1103.PubMedCrossRefGoogle Scholar
  11. 11.
    Kao JH, Hsu HM, Shau WY, et al.: Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan. J Pediatr 2001, 139:349–352.PubMedCrossRefGoogle Scholar
  12. 12.
    Chang MH, Shau WY, Chen CJ, et al.: Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA 2000, 284:3040–3042.PubMedCrossRefGoogle Scholar
  13. 13.
    Leung NW, Lai CL, Chang TT, et al.: Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001, 33:1527–1532.PubMedCrossRefGoogle Scholar
  14. 14.
    Kazim SN, Wakil SM, Khan LA, et al.: Vertical transmission of hepatitis B virus despite maternal lamivudine therapy. Lancet 2002, 359:1488–1489.PubMedCrossRefGoogle Scholar
  15. 15.
    Cheng YC: Potential use of antiviral L(-)nucleoside analogues for the prevention or treatment of viral associated cancers. Cancer Lett 2001, 162(suppl):S33-S37.PubMedCrossRefGoogle Scholar
  16. 16.
    Le Guerhier F, Pichoud C, Jamard C, et al.: Antiviral activity of beta-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine in woodchucks chronically infected with woodchuck hepatitis virus. Antimicrob Agents Chemother 2001, 45:1065–1077.PubMedCrossRefGoogle Scholar
  17. 17.
    Nishiguchi S, Shiomi S, Nakatani S, et al.: Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis. Lancet 2001, 357:196–197. This prospective, randomized, controlled study of 90 chronic HCV patients found a protective effect of interferon α on HCC development and death (risk ratios vs symptomatic treatment, 0.256 and 0.135, respectively) after 8.7 years of follow-up.PubMedCrossRefGoogle Scholar
  18. 18.
    Ikeda K, Saitoh S, Kobayashi M, et al.: Long-term interferon therapy for 1 year or longer reduces the hepatocellular carcinogenesis rate in patients with liver cirrhosis caused by hepatitis C virus: a pilot study. J Gastroenterol Hepatol 2001, 16:406–415.PubMedCrossRefGoogle Scholar
  19. 19.
    Toyoda H, Kumada T, Nakano S, et al.: Effect of the dose and duration of interferon-alpha therapy on the incidence of hepatocellular carcinoma in noncirrhotic patients with a nonsustained response to interferon for chronic hepatitis C. Oncology 2001, 61:134–142.PubMedCrossRefGoogle Scholar
  20. 20.
    Papatheodoridis GV, Papadimitropoulos VC, Hadziyannis SJ: Effect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a meta-analysis. Aliment Pharmacol Ther 2001, 15:689–698. This high-quality meta-analysis, which considered 11 studies with 2178 HCV patients, found a significant protective effect of interferon α on HCC development. Although the effect was most pronounced for sustained responders, a reduced HCC incidence in nonresponders was also found.PubMedCrossRefGoogle Scholar
  21. 21.
    Takimoto M, Ohkoshi S, Ichida T, et al.: Interferon inhibits progression of liver fibrosis and reduces the risk of hepatocarcinogenesis in patients with chronic hepatitis C: a retrospective multicenter analysis of 652 patients. Dig Dis Sci 2002, 47:170–176.PubMedCrossRefGoogle Scholar
  22. 22.
    Camma C, Giunta M, Andreone P, Craxi A: Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach. J Hepatol 2001, 34:593–602. This excellent meta-analysis considered three randomized and 15 nonrandomized controlled trials including 4614 patients and comparing interferon α treatment with no treatment. A protective effect of interferon α in HCV was identified, but the magnitude was low and related to response to interferon α. Interferon α did not affect HCC development in HBV-related cirrhosis.PubMedCrossRefGoogle Scholar
  23. 23.
    Yuen MF, Hui CK, Cheng CC, et al.: Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology 2001, 34:139–145.PubMedCrossRefGoogle Scholar
  24. 24.
    Kumada H: Long-term treatment of chronic hepatitis C with glycyrrhizin (stronger neo-minophagen C [SNMC]) for preventing liver cirrhosis and hepatocellular carcinoma. Oncology 2002, 62(suppl 1):94–100.PubMedCrossRefGoogle Scholar
  25. 25.
    The Ginseng-HCC Chemopreventive Study Osaka Group: Study on chemoprevention of hepatocellular carcinoma by ginseng: an introduction to the protocol. J Korean Med Sci 2001, 16(suppl):S70-S74.Google Scholar
  26. 26.
    Cyong JC, Ki SM, Iijima K, et al.: Clinical and pharmacological studies on liver diseases treated with Kampo herbal medicine. Am J Chin Med 2000, 28:351–360.PubMedCrossRefGoogle Scholar
  27. 27.
    Okuno M, Kojima S, Moriwaki H: Chemoprevention of hepatocellular carcinoma: concept, progress and perspectives. J Gastroenterol Hepatol 2001, 16:1329–1335.PubMedCrossRefGoogle Scholar
  28. 28.
    Sofowora GG, Choo EF, Mayo G, et al.: In vivo inhibition of human CYP1A2 activity by oltipraz. Cancer Chemother Pharmacol 2001, 47:505–510.PubMedCrossRefGoogle Scholar
  29. 29.
    Dick RA, Kwak MK, Sutter TR, Kensler TW: Antioxidative function and substrate specificity of NAD(P)H-dependent alkenal/one oxidoreductase: a new role for leukotriene B4 12-hydroxydehydrogenase/15-oxoprostaglandin 13-reductase. J Biol Chem 2001, 276:40803–40810. This study demonstrated a novel catalytic activity of NAD(P)H-dependent alkenal/one oxidoreductase (leukotriene B412-hydroxydehydrogenase): reduction of the α,β-carbon=carbon double bond of α,β-unsaturated aldehydes and ketones such as 4-hydroxy-2-nonenal. In addition, forced overexpression of the enzyme protected cells from the toxicity of 4-hydroxy-2-nonenal, a major product of lipid peroxidation.PubMedCrossRefGoogle Scholar
  30. 30.
    Kwak MK, Itoh K, Yamamoto M, et al.: Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med 2001, 7:135–145. This investigation characterized the expression patterns of over a dozen genes inducible by 3H-1,2-dithiole-3-thione in both wild-type and nrf2-disrupted mice. Nrf2 was found to play a central regulatory role in the constitutive and dithiolthione-inducible expression of multiple phase 2 and antioxidative enzymes.PubMedGoogle Scholar
  31. 31.
    Egner PA, Wang JB, Zhu YR, et al.: Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer. Proc Natl Acad Sci U S A 2001, 98:14601–14606. This double-blind, placebo-controlled study of chlorophyllin (100 mg three times a day for 4 months) in 180 residents of Qidong, People’s Republic of China, demonstrated a 55% reduction in urinary aflatoxin-DNA adducts (P=0.036).PubMedCrossRefGoogle Scholar
  32. 32.
    Walton M, Egner P, Scholl PF, et al.: Liquid chromatography electrospray-mass spectrometry of urinary aflatoxin biomarkers: characterization and application to dosimetry and chemoprevention in rats. Chem Res Toxicol 2001, 14:919–926.PubMedCrossRefGoogle Scholar
  33. 33.
    Fukushima S, Takada N, Wanibuchi H, et al.: Suppression of chemical carcinogenesis by water-soluble organosulfur compounds. J Nutr 2001, 131:1049S-1053S.PubMedGoogle Scholar
  34. 34.
    Yang CF, Liu J, Wasser S, et al.: Inhibition of ebselen on aflatoxin B(1)-induced hepatocarcinogenesis in Fischer 344 rats. Carcinogenesis 2000, 21:2237–2243.PubMedCrossRefGoogle Scholar
  35. 35.
    Watanabe T, Sugie S, Okamoto K, et al.: Chemopreventive effects of scordinin on diethylnitrosamine and phenobarbital-induced hepatocarcinogenesis in male F344 rats. Jpn J Cancer Res 2001, 92:603–609.PubMedGoogle Scholar
  36. 36.
    Rajeshkumar NV, Kuttan R: Inhibition of N-nitrosodiethylamine-induced hepatocarcinogenesis by Picroliv. J Exp Clin Cancer Res 2000, 19:459–465.PubMedGoogle Scholar
  37. 37.
    Ahmed S, Rahman A, Mathur M, et al.: Anti-tumor promoting activity of Asteracantha longifolia against experimental hepatocarcinogenesis in rats. Food Chem Toxicol 2001, 39:19–28.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu J, Yang CF, Wasser S, et al.: Protection of salvia miltiorrhiza against aflatoxin-B1-induced hepatocarcinogenesis in Fischer 344 rats dual mechanisms involved. Life Sci 2001, 69:309–326.PubMedCrossRefGoogle Scholar
  39. 39.
    Maruyama S, Nagasue N, Dhar DK, et al.: Preventive effect of FK143, a 5alpha-reductase inhibitor, on chemical hepatocarcinogenesis in rats. Clin Cancer Res 2001, 7:2096–2104.PubMedGoogle Scholar
  40. 40.
    Qin G, Ning Y, Lotlikar PD: Chemoprevention of aflatoxin B1-initiated and carbon tetrachloride-promoted hepatocarcinogenesis in the rat by green tea. Nutr Cancer 2000, 38:215–222.PubMedCrossRefGoogle Scholar
  41. 41.
    Hosaka S, Kawa S, Aoki Y, et al.: Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene. Food Chem Toxicol 2001, 39:557–561.PubMedCrossRefGoogle Scholar
  42. 42.
    Kaji I, Tatsuta M, Iishi H, et al.: Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association. Int J Cancer 2001, 93:441–444.PubMedCrossRefGoogle Scholar
  43. 43.
    Kakizaki S, Takagi H, Fukusato T, et al.: Effect of alphatocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine. Int J Vitam Nutr Res 2001, 71:261–267.PubMedCrossRefGoogle Scholar
  44. 44.
    Basak R, Bhattacharya R, Chatterjee M: 1 alpha,25-Dihydroxyvitamin D(3) inhibits rat liver ultrastructural changes in diethylnitrosamine-initiated and phenobarbital promoted rat hepatocarcinogenesis. J Cell Biochem 2001, 81:357–367.PubMedCrossRefGoogle Scholar
  45. 45.
    Silveira ER, Naves MM, Vannucchi H, et al.: Vitamin A and alltrans and 9-cis retinoic acids inhibit cell proliferation during the progression phase of hepatocarcinogenesis in Wistar rats. Nutr Cancer 2001, 39:244–251.PubMedCrossRefGoogle Scholar
  46. 46.
    Jackson PE, Qian GS, Friesen MD, et al.: Specific p53 mutations detected in plasma and tumors of hepatocellular carcinoma patients by electrospray ionization mass spectrometry. Cancer Res 2001, 61:33–35.PubMedGoogle Scholar
  47. 47.
    Tannapfel A, Busse C, Weinans L, et al.: INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 2001, 20:7104–7109.PubMedCrossRefGoogle Scholar
  48. 48.
    Azechi H, Nishida N, Fukuda Y, et al.: Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas. Oncology 2001, 60:346–354.PubMedCrossRefGoogle Scholar
  49. 49.
    Kaneto H, Sasaki S, Yamamoto H, et al.: Detection of hypermethylation of the p16(INK4A) gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut 2001, 48:372–377.PubMedCrossRefGoogle Scholar
  50. 50.
    Bugni JM, Poole TM, Drinkwater NR: The little mutation suppresses DEN-induced hepatocarcinogenesis in mice and abrogates genetic and hormonal modulation of susceptibility. Carcinogenesis 2001, 22:1853–1862.PubMedCrossRefGoogle Scholar
  51. 51.
    Klocke R, Bartels T, Jennings G, et al.: Lack of p53 accelerates hepatocarcinogenesis in transgenic mice constitutively overexpressing c-myc in the liver. FASEB J 2001, 15:1404–1406.PubMedGoogle Scholar
  52. 52.
    Kwun HJ, Jung EY, Ahn JY, et al.: p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3. J Gen Virol 2001, 82:2235–2241.PubMedGoogle Scholar
  53. 53.
    Hatanaka Y, Nakae D, Mutai M, et al.: Decreased expression of Bcl-x protein during hepatocarcinogenesis induced exogenously and endogenously in rats. Jpn J Cancer Res 2001, 92:1270–1277.PubMedGoogle Scholar
  54. 54.
    Baba M, Iishi H, Tatsuta M: Transfer of bcl-xs plasmid is effective in preventing and inhibiting rat hepatocellular carcinoma induced by N-nitrosomorpholine. Gene Ther 2001, 8:1149–1156.PubMedCrossRefGoogle Scholar
  55. 55.
    Vogel A, Kneip S, Barut A, et al.: Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene. Gastroenterology 2001, 121:1136–1144. This German case-control study involved 59 cancer patients and 70 control subjects. The uridine 5′-diphosphate-glucuronosyltransferase allele UGT1A7*3, which encodes a protein with low carcinogen detoxification activity, was significantly associated with HCC.PubMedCrossRefGoogle Scholar
  56. 56.
    Sun CA, Wang LY, Chen CJ, et al.: Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan. Carcinogenesis 2001, 22:1289–1294. This Taiwanese case-control study of chronic HBV carriers involved 79 HCC patients and 149 control subjects. A statistically significant correlation between HCC risk and serum AFB1-albumin adducts was found. In addition, the effect of aflatoxin exposure on HCC risk was more pronounced among HBV carriers with the GSTT1 null genotype (P=0.03).PubMedCrossRefGoogle Scholar
  57. 57.
    Schwarz KB, Kew M, Klein A, et al.: Increased hepatic oxidative DNA damage in patients with hepatocellular carcinoma. Dig Dis Sci 2001, 46:2173–2178.PubMedCrossRefGoogle Scholar
  58. 58.
    Kitada T, Seki S, Iwai S, et al.: In situ detection of oxidative DNA damage, 8-hydroxydeoxyguanosine, in chronic human liver disease. J Hepatol 2001, 35:613–618.PubMedCrossRefGoogle Scholar
  59. 59.
    Moriya K, Nakagawa K, Santa T, et al.: Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 2001, 61:4365–4370.PubMedGoogle Scholar
  60. 60.
    Zhou ZQ, Manguino D, Kewitt K, et al.: Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O6-methylguanine-DNA methyltransferase. Proc Natl Acad Sci U S A 2001, 98:12566–12571.PubMedCrossRefGoogle Scholar
  61. 61.
    Walter CA, Zhou ZQ, Manguino D, et al.: Health span and life span in transgenic mice with modulated DNA repair. Ann NY Acad Sci 2001, 928:132–140.PubMedCrossRefGoogle Scholar
  62. 62.
    Takahashi Y, Nakatsuru Y, Zhang S, et al.: Enhanced spontaneous and aflatoxin-induced liver tumorigenesis in xeroderma pigmentosum group A gene-deficient mice. Carcinogenesis 2002, 23:627–633.PubMedCrossRefGoogle Scholar
  63. 63.
    Matsushima-Nishiwaki R, Okuno M, Adachi S, et al.: Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. Cancer Res 2001, 61:7675–7682. In surgically resected HCC and in HuH17 human HCC-derived cells, RXR-α was phosphorylated at serine 260 by MAPK. Phosphorylated RXR-α lost its transactivation activity, was resistant to degradation, and was associated with increased proliferation.PubMedGoogle Scholar
  64. 64.
    Okuno M, Sano T, Matsushima-Nishiwaki R, et al.: Apoptosis induction by acyclic retinoid: a molecular basis of ‘clonal deletion’ therapy for hepatocellular carcinoma. Jpn J Clin Oncol 2001, 31:359–362.PubMedCrossRefGoogle Scholar
  65. 65.
    Feng DY, Zheng H, Tan Y, Cheng RX: Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol 2001, 7:33–36.PubMedGoogle Scholar
  66. 66.
    Tarn C, Lee S, Hu Y, et al.: Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes. J Biol Chem 2001, 276:34671–34680.PubMedCrossRefGoogle Scholar
  67. 67.
    Lara-Pezzi E, Roche S, Andrisani OM, et al.: The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene 2001, 20:3323–3331.PubMedCrossRefGoogle Scholar
  68. 68.
    Tu H, Bonura C, Giannini C, et al.: Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. Cancer Res 2001, 61:7803–7810.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Kathryn Z. Guyton
    • 1
  • Thomas W. Kensler
    • 1
  1. 1.Department of Environmental Health SciencesBloomberg School of Public Health, Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations