Protective Effects of [6]-Paradol on Histological Lesions and Immunohistochemical Gene Expression in DMBA Induced Hamster Buccal Pouch Carcinogenesis

  • Published : 2013.05.30


Background: The search for naturally occurring agents in routinely consumed foods that may inhibit cancer development is of high priority. [6]-Paradol is a pungent phenolic bioactive component from ginger with welldocumented health promoting antioxidant, antimutagenic, antigenotoxic and anti-inflammatory properties. However, anticarcinogenic effects have yet to be fully explored. The objectives of the present study were therefore to assess protective effects against 7,12-dimethylbenz(a)anthracene (DMBA) induced buccal pouch carcinogenesis in male golden Syrian hamsters. Methods: Oral squamous cell carcinomas developed in the left buccal pouch of hamsters on painting with 0.5% of DMBA, three times in a week. To assess the apoptotic associated gene expressing potential of [6]-paradol, it was orally administered to DMBA treated hamsters on alternate days from DMBA painting for 14 weeks. Results: We observed 100% tumor formation with marked levels of neoplastic changes and altered the expression of apoptotic associated gene (p53, bcl-2, caspase-3 and TNF-${\alpha}$) was observed in the DMBA alone painted hamsters as compared to control hamsters. Oral administration of [6]-paradol at a dose of 30 mg/kg b.wt to DMBA treated animals on alternative days for 14 weeks significantly reduced the neoplastic changes and improved the status of apoptosis associated gene expression. Conclusion: These observations confirmed that [6]-paradol acts as a tumor suppressing agent against DMBA induced oral carcinogenesis. We also conclude that [6]-paradol also effectively enhances apoptosis- associated gene expression in DMBA treated animals.


  1. Bishayee A, Mbimba T, Thoppil RJ, et al (2011). Anthocyanin rich black currant (Ribes nigrum L.) extract affords chemoprevention against diethylnitrosamine induced hepatocellular carcinogenesis in rats. J Nutr Biochem, 22, 1035-46.
  2. Bourdon JC (2007). p53 and its isoforms in cancer. Br J Cancer, 97, 277-82.
  3. Bratton SB, Cohen GM (2001). Caspase cascades in chemically induced apoptosis. Adv Exp Med Biol, 500, 407-20.
  4. Cotran RS, Kumar V, Robbins SL, Pathologic basis of disease. (Philadelphia, W.B. Saunders, 1994) p. 1129.
  5. Coultas L, Strasser A (2003). The role of the Bcl-2 protein family in cancer. Semin Cancer Biol, 13, 115-23.
  6. Crowe DL, Sinha UK (2006). p53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines. Head Neck, 28, 15-23.
  7. Cruz I, Napier SS, Van der Waal I, et al (2002). Specific p53 immunostaining patterns are associated with smoking habits in patients with oral squamous cell carcinomas. J Clin Pathol, 55, 834-40.
  8. Elliott MJ, Maini RN, Feldmann M, et al (1994). Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet, 344, 1125-7.
  9. Englaro W, Bahadoran P, Bertolotto C, et al (1999). Tumor necrosis factor alpha-mediated inhibition of melanogenesis is dependent on nuclear factor kappa B activation. Oncogene, 18, 1553-9.
  10. Fraser A, Evan G (1996). A license to kill. Cell, 85, 781-4.
  11. Hasnan J, Suhaila A, Mogana Das M, Fauziah M (2012). Expression of bax and bcl-2 in tumour cells and blood vessels of breast cancer and their association with angiogenesis and hormonal receptors. Asian Pac J Cancer Prev, 13, 3857-62.
  12. He Z, Ma WY, Hashimoto T, et al (2003). Induction of apoptosis by caffeine is mediated by the p53, Bax, and caspase 3 pathways. Cancer Res, 63, 4396-401.
  13. Jemal R, Siegel E, Ward Y, et al (2009). Cancer statistics, 2009. CA Cancer J Clin, 59, 225-49.
  14. Keum YS, Kim J, Lee KH, et al (2002). Induction of apoptosis and caspase-3 activation by chemopreventive [6]-paradol and structurally related compounds in KB cells. Cancer Lett, 177, 41-7.
  15. Kim DH, Kundu JK, Surh YJ (2011). Redox modulation of p53: mechanisms and functional significance. Mol Carcinog, 50, 222-34.
  16. Kischkel FC, Lawrence DA, Chuntharapai A, et al (2000). Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity, 12, 611-20.
  17. Leibowitz B, Yu J (2010). Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther, 9, 417-22.
  18. Locksley HD, Rainey DK, Rohan TA (1972). Pungent compounds. Part I. An improved synthesis of the paradols (alkyl 4-hydroxy-3-methoxyphenethyl ketones) and an assessment of their pungency. J Chem Soc Perkin Trans, 1, 3001-6.
  19. Martinou JC, Youle RJ (2011). Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell, 21, 92-101
  20. Marur S, D'Souza G, Westra WH, Forastiere AA (2010). HPV associated head and neck cancer: a virus related cancer epidemic. Lancet Oncol, 11, 781-99.
  21. Mitselou A, Karapiperides D, Nesseris I, Vougiouklakis T, Agnantis NJ (2010). Altered expression of cell cycle and apoptotic proteins in human liver pathologies. Anticancer Res, 30, 4493-501.
  22. Muller-Ladner U, Alten R, Heiligenhaus A, et al (2009). TNF alpha related chronic inflammatory diseases - a new multiple diseases bridging concept. Dtsch Med Wochenschr, 134, 2132-6.
  23. Munshi A, Pappas G, Honda T, et al (2001). TRAIL (APO-2L) induces apoptosis in human prostate cancer cells that is inhibitable by Bcl-2. Oncogene, 20, 3757-65.
  24. Nakagawa K, Yamamura K, Maeda S, Ichihashi M (1994). Bcl-2 expression in epidermal keratinocytic diseases. Cancer, 74, 1720-724.<1720::AID-CNCR2820740613>3.0.CO;2-T
  25. Porter AG, Janicke RU (1996). Emerging roles of caspase-3 in apoptosis. Cell Death Differ, 6, 99-104
  26. Prunet C, Lemaire SE, Menetrier F (2005). Activation of caspase-3 dependent and independent pathways during 7-ketocholesterol and beta hydroxycholesterol induced cell death: a morphological and biochemical study. J Biochem Mol Toxicol, 19, 311-26.
  27. Ramirez-Mares MV, Chandra S, De Mejia EG (2004). In vitro chemopreventive activity of Camellia sinensis, Ilex paraguariensis and Ardisia compressa tea extracts and selected polyphenols. Mutat Res, 554, 53-5.
  28. Ramos-Vara JA (2005). Technical aspects of immunohistochemistry. Vet Pathol, 42, 405-26.
  29. Rivlin N, Brosh R, Oren M, Rotter V (2011). Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes & Cancer, 2, 466-74
  30. Rundle A, Tang D, Hibshoosh H, et al (2000). The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer. Carcinogenesis, 21, 128-89.
  31. Salley JJ (1954). Experimental carcinogenesis in the cheek pouch of the Syrian Hamster. J Dent Res, 33, 253-62.
  32. Satoh M, Kondo Y, Mita M, et al (1993). Prevention of carcinogenicity of anticancer drugs by metallothionein induction. Cancer Res, 53, 4767-78.
  33. Shirkoohi R, Fujita HG, Darmanin S, Takimoto M (2012). Gelsolin induces promonocytic leukemia differentiation accompanied by upregulation of p21CIP1. Asian Pac J Cancer Prev, 13, 4827-834
  34. Smith EM, Rubenstein LM, Haugen TH (2010). Tobacco and alcohol use increases the risk of both HPV-associated and HPV independent head and neck cancers. Cancer Causes Control, 2, 1369-378
  35. Suresh K, Manoharan S, Arokia Vijayaanand M, Sugunadevi G (2010). Chemopreventive and antioxidant efficacy of (6)-paradol in 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. Pharamacol Rep, 62, 1178-85.
  36. Takiar R, Nadayil D, Nandakumar A (2010). Projections of number of cancer cases in India (2010-2020) by cancer groups. Asian Pac J Cancer Prev, 11, 1045-59.
  37. Takuji T, Mayu T, Takahiro T (2011). Oral carcinogenesis and oral cancer chemoprevention. A Review Pathol Res Int, 1, 10.
  38. Tanaka T (1997). Chemoprevention of human cancer: biology and therapy. Crit Rev Oncol Hematol, 25, 139-74.
  39. Thomson M, Al-Qattan KK, Al-Sawan SM, et al (2002). The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Essent Fatty Acids, 67, 475-8.
  40. White B (2007). Ginger: an overview. Amm Fam Physician, 75, 1689-91.

Cited by

  1. Spices for Prevention and Treatment of Cancers vol.8, pp.8, 2016,
  2. Modulating effect of hesperetin on the molecular expression pattern of apoptotic and cell proliferative markers in 7,12-dimethylbenz(a)anthracene-induced oral carcinogenesis pp.1744-4160, 2019,