Skip to main content

Anticancer effect of ursolic acid stearoyl glucoside in chemically induced hepatocellular carcinoma

Journal of Physiology and Biochemistry volume 69, pages 687–695 (2013)Cite this article

Abstract

Hepatocellular carcinoma is one of the leading causes of death in cancer and yet no drug has proven to be a successful candidate for its treatment in advanced stages. Ursolic acid stearoyl glucoside (UASG) is a newly discovered triterpene in Lantana camara and there lies a possibility that it possess anti-hepatocellular carcinoma property. In the present study, we induced hepatocellular carcinoma in Wistar rats by diethylnitrosamine (DENA) and treated it with ursolic acid stearoyl glucoside. The ability to treat hepatocellular carcinoma was measured by comparing biochemical serum markers such as serum alanine aminotransferase, serum aspartate aminotransferase, serum alkaline phosphatase, and the specific marker for hepatocellular carcinoma, alpha fetoprotein. The histological studies of the livers were also performed. The results have shown significant elevated levels of these parameters as compared to normal control and the drug receiving groups have shown significant reduction in these marker levels. Histopathological studies also indicated the reduced liver damage in drug-treated groups. It was noted that a significant and dose-dependent reversal of DENA-diminished activity of antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, and the reduced DENA-elevated level of lipid peroxidation (LPO) with a marked change. UASG significantly suppressed free radical formation by scavenging the hydroxyl radicals. It also modulates the levels of LPO and markedly increases the endogenous antioxidant enzymes level in DENA-induced hepatocellular carcinogenesis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Alonso-Castro AJ, Villarreal ML, Salazar-Olivo LA, Gomez-Sanchez M, Dominguez F, Garcia-Carranca A (2011) Mexican medicinal plants used for cancer treatment: pharmacological, phytochemical and ethnobotanical studies. J Ethnopharmacol 133:945–972

    PubMed  Article  CAS  Google Scholar 

  2. Al-Rejaie SS, Aleisa AM, Al-Yahya AA, Bakheet SA, Alsheikh A, Fatani AG (2009) Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats. World J Gastroenterol 15:1373–1380

    PubMed  Article  CAS  Google Scholar 

  3. Baek JH, Lee YS, Kang CM, Kim JA, Kwon KS, Son HC, Kim KW (1997) Intracellular Ca+2 release mediates ursolic acid-induced apoptosis in human leukaemic HL-60 cell. Int J Cancer 73:725–728

    PubMed  Article  CAS  Google Scholar 

  4. Bravi F, Bosetti C, Tavani A, Bagnardi V, Gallus S, Negri E, Franceschi S, La Vecchia C (2007) Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 46(2):430–435

    PubMed  Article  Google Scholar 

  5. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1226

    PubMed  Article  Google Scholar 

  6. Cardenas C, Quesada AR, Medina MA (2004) Effects of ursolic acid on different steps of the angiogenesis process. Biochem Biophys Res Commun 320:402–408

    PubMed  Article  CAS  Google Scholar 

  7. Chakraborty T, Chatterjee A, Rana A, Dhachinamoorthi D, Kumar PA, Chatterjee M (2007) Carcinogen-induced early molecular events and its implication in the initiation of chemical hepatocarcinogenesis in rats: chemopreventive role of vanadium on this process. Biochim Biophys Acta 1772:48–59

    PubMed  Article  CAS  Google Scholar 

  8. Clawson GA (1989) Mechanism of carbon tetrachloride hepatotoxicity. Pathol Immunopathol Res 8:104–112

    PubMed  Article  CAS  Google Scholar 

  9. Coleman WB (2003) Mechanisms of human hepatocarcinogenesis. Curr Mol Med 3(6):573–588

    PubMed  Article  CAS  Google Scholar 

  10. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127

    PubMed  Article  CAS  Google Scholar 

  11. El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126:460–468

    PubMed  Article  Google Scholar 

  12. Esterbauer H, Chesseman KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxy-nonenal. Methods Enzymol 186:407–421

    PubMed  Article  CAS  Google Scholar 

  13. Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687

    PubMed  Article  CAS  Google Scholar 

  14. Ferlay J, Shin HR, Bray F, Forman D, Mathers C (2010) GLOBOCAN 2008, cancer incidence and mortality worldwide: no. 10. Lyon, France: International Agency for Research on Cancer. Int J Cancer 127:2893–2917

    PubMed  Article  CAS  Google Scholar 

  15. Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J (2009) Angiogenesis in liver disease. J Hepatol 50:604–620

    PubMed  Article  CAS  Google Scholar 

  16. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    PubMed  Article  CAS  Google Scholar 

  17. Harmand PO, Duval R, Liagre B, Jayat-Vignoles C, Beneytout JL, Delage C, Simon A (2003) Ursolic acid induces apoptosis through caspase-3 activation and cell cycle arrest in HaCat cells. Int J Oncol 23:105–112

    PubMed  CAS  Google Scholar 

  18. Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88

    PubMed  Article  CAS  Google Scholar 

  19. Hietanen E, Ahotupa M, Bartsch H (1987) Lipid peroxidation and chemically induced cancer in rats fed lipid rich diet. In: Lapis K, Kcharst S (eds) Carcinogenesis and tumor progression, vol. 4. Akademiaikiado, Budapest, pp 9–16

    Google Scholar 

  20. Hollosy F, Meszaros G, Bokonyi G, Idei M, Seprodi A, Szende B, Keri G (2000) Cytostatic, cytotoxic and protein tyrosine kinase inhibitory activity of ursolic acid in A431 human tumour cells. Anticancer Res 20:4653–4670

    Google Scholar 

  21. Huang MT, Ho CT, Wang ZY, Ferraro T, Lou YR, Stauber K, Ma W, Georgiadis C, Laskin JD, Conney AH (1994) Inhibition of skin tumourigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer Res 54:701–708

    PubMed  CAS  Google Scholar 

  22. Kazmi I, Gaurav G, Afzal M, Anwar F (2012) Anticonvulsant and depressant-like activity of ursolic acid stearoyl glucoside isolated from Lantana camara L. (Verbanaceae). Asian Pac J Trop Dis 2(1):S453–S456

    Article  Google Scholar 

  23. Kazmi I, Rahman M, Afzal M, Gupta G, Saleem S, Afzal O, Shaharyar MA, Nautiyal U, Ahmed S, Anwar F (2012) Anti-diabetic potential of ursolic acid stearoyl glucoside: a new triterpenic gycosidic ester from Lantana camara. Fitoterapia 83:142–146

    PubMed  Article  CAS  Google Scholar 

  24. Kazmi I, Afzal M, Gupta G, Anwar F (2012) Antiepileptic potential of ursolic acid stearoyl glucoside by GABA receptor stimulation. CNS Neurosci Ther 18(9):799–800

    PubMed  Article  Google Scholar 

  25. Kazmi I, Gupta G, Afzal M, Rahman M, Anwar F (2012) Pharmacological evaluation of anxiolytic activity of ursolic acid stearoyl glucoside isolated from Lantana camara. CNS Neurosci Ther 18(8):707–708

    PubMed  Article  CAS  Google Scholar 

  26. Kim DK, Baek JH, Kang CM, Yoo MA, Sung JW, Chung HY, Kim ND, Choi YH, Lee SH, Kim KW (2000) Apoptotic activity of ursolic activity may correlate with the inhibition of initiation of DNA replication. Int J Cancer 87:629–636

    PubMed  Article  CAS  Google Scholar 

  27. Klaunig JE, Kamendulis LM (2004) The role of oxidative stress in carcinogenesis. Ann Rev Pharmacol Toxicol 44:239–267

    Article  CAS  Google Scholar 

  28. Li W, Tan D, Zhang Z, Liang JJ, Brown RE (2008) Activation of Akt-mTOR signaling in angiogenesis in hepatocellular carcinoma. Oncol Rep 20(4):713–719

    PubMed  Google Scholar 

  29. Liu J (1995) Pharmacology of oleanoic acid and ursolic acid. J Ethnopharmacol 49:57–68

    PubMed  Article  CAS  Google Scholar 

  30. Manez S, Recio MC, Giner RM, Rios JL (1997) Effect of selected triterpenoids on chronic dermal inflammation. Eur J Pharmacol 334:103–105

    PubMed  Article  CAS  Google Scholar 

  31. Manu KA, Kuttan G (2008) Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-κB mediated activation of bcl-2 in B16F-10 melanoma cells. Int Immunopharmacol 8:974–981

    PubMed  Article  CAS  Google Scholar 

  32. Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS (2005) Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 42:218–224

    PubMed  Article  CAS  Google Scholar 

  33. Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM (2009) Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 25(3):86–94

    Article  Google Scholar 

  34. Najid A, Simon A, Cook J, Chable-Rabinovitch H, Delage C, Chulia AJ, Rigaud M (1992) Characterisation of ursolic acid as a lipoxygenase and cyclo-oxygenase inhibitor using macrophages, platelets and differentiated HL60 leukaemic cells. FEBS Lett 299:213–217

    PubMed  Article  CAS  Google Scholar 

  35. Newell P, Villanueva A, Friedman SL, Koike K, Llovet JM (2008) Experimental models of hepatocellular carcinoma. J Hepatol 48:858–879

    PubMed  Article  CAS  Google Scholar 

  36. Ovesna Z, Kozics K, Slamenova D (2006) Protective effects of ursolic acid and oleanolic acid in leukemic cells. Mutat Res 600:131–137

    PubMed  Article  CAS  Google Scholar 

  37. Pang R, Poon RTP (2006) Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett 242:151–167

    PubMed  Article  CAS  Google Scholar 

  38. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    PubMed  Article  Google Scholar 

  39. Peng JW, Cheng AL, Hsu C, Chen CM (2010) Clinical development and future direction for the treatment of hepatocellular carcinoma. J Exp Clin Med 2(3):93–103

    Article  Google Scholar 

  40. Plaa GL, Hewitt WR (1989) Detection and evaluation of chemically induced liver injury. In: Wallace Hyes A (ed) Principle and methods of toxicology, 2nd edn. Raven, New York, p 399

    Google Scholar 

  41. Rajeshkumar NV, Kuttan R (2000) Inhibition of N-nitrosodiethylamine-induced hepatocarcinogenesis by Picroliv. J Exp Clin Cancer Res 19:459–465

    PubMed  CAS  Google Scholar 

  42. Robak J, Glyglewsi RJ (1988) Flavonoids are scavengers of superoxide anions. Biochem Pharmacol 37:837–841

    PubMed  Article  CAS  Google Scholar 

  43. Shao JW, Dai YC, Xue JP, Wang JC, Lin FP, Guo YH (2011) In vitro and in vivo anticancer activity evaluation of ursolic acid derivatives. Eur J Med Chem 46:2652–2661

    PubMed  Article  CAS  Google Scholar 

  44. Sherman M (2010) Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 30:3–16

    PubMed  Article  CAS  Google Scholar 

  45. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-KB activation induced by carcinogenic agents through suppression of. I KBa kinase and p65 phosphorylation: correlation with down-regulation of cyclo-oxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 62:4375–4383

    Google Scholar 

  46. Sohn KH, Lee HY, Chung HY, Young HS, Yi SY, Kim KW (1995) Anti-angiogenic activity of triterpene acids. Cancer Lett 94:213–218

    PubMed  Article  CAS  Google Scholar 

  47. Subbaramaiah K, Michaluart P, Sporn MB, Dannenberg AJ (2000) Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells. Cancer Res 60:2399–2404

    PubMed  CAS  Google Scholar 

  48. Suh N, Honda T, Finlay HJ, Barchowsky A, Williams C, Benoit NE, Xie QW, Nathan C, Gribble GW, Sporn MB (1998) Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res 58:717–723

    PubMed  CAS  Google Scholar 

  49. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:1–40

    PubMed  Article  CAS  Google Scholar 

  50. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM (2007) Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 27:55–76

    PubMed  Article  CAS  Google Scholar 

  51. Wright LM, Kreikemeier JT, Fimmel CJ (2007) A concise review of serum markers for hepatocellular cancer. Cancer Detect Prev 31:35–44

    PubMed  Article  CAS  Google Scholar 

  52. Yan SL, Huang CY, Wu ST, Yin MC (2010) Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol Vitr 24:842–848

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Authors are thankful to the Department of Pharmacology, Siddhartha Institute of Pharmacy, Dehradun for the all possible help it has provided for conducting the research.

Author information

Authors and Affiliations

  1. Siddhartha Institute of Pharmacy, Dobachi, Near IT Park, Dehra Dun, 248001, Uttarakhand, India

    Imran Kazmi, Anil Raj Narooka, Muhammad Afzal, Rajbala Singh, Fahad A. Al-Abbasi, Aftab Ahmad & Firoz Anwar

  2. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia

    Fahad A. Al-Abbasi

  3. Health Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia

    Aftab Ahmad

Authors
  1. Imran Kazmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anil Raj Narooka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhammad Afzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rajbala Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fahad A. Al-Abbasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aftab Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Firoz Anwar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Muhammad Afzal or Firoz Anwar.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kazmi, I., Narooka, A.R., Afzal, M. et al. Anticancer effect of ursolic acid stearoyl glucoside in chemically induced hepatocellular carcinoma. J Physiol Biochem 69, 687–695 (2013). https://doi.org/10.1007/s13105-013-0245-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-013-0245-8

Keywords

  • Hepatocellular carcinoma
  • Diethylnitrosamine
  • Ursolic acid stearoyl glucoside
  • Histology
  • Biochemical analysis
  • Free radical scavenger