Investigational New Drugs

, Volume 28, Issue 4, pp 466–471 | Cite as

Tea polyphenols inhibit cyclooxygenase-2 expression and block activation of nuclear factor-kappa B and Akt in diethylnitrosoamine induced lung tumors in Swiss mice

  • Preeti Roy
  • Nidhi Nigam
  • Madhulika Singh
  • Jasmine George
  • Smita Srivastava
  • Hasnain Naqvi
  • Yogeshwer Shukla


Background Due to lack of validated screening methods and hence poor prognosis, treatment of lung cancer has not still improved up to the expectations. Therefore, risk of lung cancer needs to be minimized by efficient preventive measures. Tea (Camellia sinensis) and its bioactive polyphenols have been associated with prevention of human cancer for several organs. Thus, intake of tea polyphenols seems to be a viable mean to control lung cancer burden. In the present study, we studied the chemopreventive effects of green tea polyphenols (GTP) and black tea polyphenols (BTP) against diethylnitrosoamine (DEN) induced lung tumors in Swiss albino mice. Results Chemopreventive potential of tea polyphenols, was recorded as evident by, low incidence of alveologenic tumors in lungs of animals at tested doses (0.1% and 0.2% of both GTP and BTP) when compared with DEN (20 mg/kg b wt) treated animals. As a mechanism of cancer chemoprevention cellular signaling pathways were also targeted. GTP and BTP treatment inhibited the expression of Akt, cyclooxygenase-2 and inactivated nuclear factor-kappa B via blocking phosphorylation and subsequent degradation of IκBα. Conclusion Thus, the study suggests that polyphenolic constituents of both cultivars of tea, i.e. green and black, have chemopreventive effects in DEN induced lung tumorigenesis in Swiss albino mice.


Chemoprevention Tea polyphenols Lung tumor Cox-2 NF-ĸB Akt 



Authors are thankful to Director, Indian Institute of Toxicology Research, Lucknow for his keen interest in the study. Authors are also thankful to Department of Biotechnology (India) and Council of Scientific and Industrial Research, New Delhi for funding this work from NWP-17. Thanks are also due to Indfrag chemical company, Bangalore, India for providing tea polyphenols. The computer aided support of Ms. Babita Singh is also gratefully acknowledged.


  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96. doi: 10.3322/CA.2007.0010 CrossRefPubMedGoogle Scholar
  2. 2.
    Behera D, Balamugesh T (2004) Lung cancer in India. Indian J Chest Dis Allied Sci 46:269–281PubMedGoogle Scholar
  3. 3.
    Gargiullo P, Wingo PA, Coates RJ, Thompson TD (2002) Recent trends in mortality rates for four major cancers, by sex and race/ethnicity-United States. MMWR Morb Mortal Wkly Rep 51:49–53Google Scholar
  4. 4.
    Bunn PA Jr, Soriano A, Johnson G, Heasley L (2000) New therapeutic strategies for lung cancer: biology and molecular biology come of age. Chest 117:163S–168S. doi: 10.1378/chest.117.4_suppl_1.163S CrossRefPubMedGoogle Scholar
  5. 5.
    Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, Della Porta G, Pierotti MA (1992) Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res 52:6079–6082PubMedGoogle Scholar
  6. 6.
    Yun TK, Sung-Ho K, Yun-Sil L (1995) Trial of a new medium term model using benzo(a) pyrene induced lung tumor in newborn mice. Anticancer Res 15:839–846PubMedGoogle Scholar
  7. 7.
    Greenwald P (2005) Lifestyle and medical approaches to cancer prevention. Recent Results Cancer Res 166:1–15. doi: 10.1007/3-540-26980-0_1 CrossRefPubMedGoogle Scholar
  8. 8.
    Wistuba II, Lam S, Behrens C, Virmani AK, Fong KM, LeRiche J, Samet JM, Srivastava S, Minna JD, Gazdar AF (1997) Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst 89:1366–1373. doi: 10.1093/jnci/89.18.1366 CrossRefPubMedGoogle Scholar
  9. 9.
    Kassie F, Anderson LB, Scherber R, Yu N, Lahti D, Upadhyaya P, Hecht SS (2007) Indole-3-carbinol inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone plus benzo(a) pyrene-induced lung tumorigenesis in A/J mice and modulates carcinogen-induced alterations in protein levels. Cancer Res 67:6502–6511. doi: 10.1158/0008-5472.CAN-06-4438 CrossRefPubMedGoogle Scholar
  10. 10.
    Berge G, Øvrebø S, Eilertsen E, Haugen A, Mollerup S (2004) Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene. Br J Cancer 91:1380–1383. doi: 10.1038/sj.bjc.6602125 CrossRefPubMedGoogle Scholar
  11. 11.
    Siddiqui IA, Afaq F, Adhami VM, Ahmad N, Mukhtar H (2004) Antioxidants of the beverage tea in promotion of human health. Antioxid Redox Signal 6:571–582. doi: 10.1089/152308604773934323 CrossRefPubMedGoogle Scholar
  12. 12.
    Chandra Mohan KV, Hara Y, Abraham SK, Nagini S (2005) Comparative evaluation of the chemopreventive efficacy of green and black tea polyphenols in the hamster buccal pouch carcinogenesis model. Clin Biochem 38:879–886. doi: 10.1016/j.clinbiochem.2005.06.011 CrossRefPubMedGoogle Scholar
  13. 13.
    Kavanagh KT, Hafer LJ, Kim DW, Mann KK, Sherr DH, Rogers AE, Sonenshein GE (2001) Green tea extracts decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture. J Cell Biochem 82:387–398. doi: 10.1002/jcb.1164 CrossRefPubMedGoogle Scholar
  14. 14.
    Naik P, Karrim J, Hanahan D (1996) The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev 10:2105–2116. doi: 10.1101/gad.10.17.2105 CrossRefPubMedGoogle Scholar
  15. 15.
    Hong MY, Chang WC, Chapkin RS, Lupton JR (1997) Relationship among colonocyte proliferation, differentiation and apoptosis as a function of diet and carcinogen. Nutr Cancer 28:20–29CrossRefPubMedGoogle Scholar
  16. 16.
    DuBois RN, Shao J, Tsujii M, Sheng H, Beauchamp RD (1996) G1 delay in cells overexpressing prostaglandin endoperoxide synthase-2. Cancer Res 56:733–737PubMedGoogle Scholar
  17. 17.
    Dannenberg AJ, Subbaramaiah K (2003) Targeting cyclooxygenase- 2 in human neoplasia: rationale and promise. Cancer Cell 4:431–436. doi: 10.1016/S1535-6108(03)00310-6 CrossRefPubMedGoogle Scholar
  18. 18.
    Verma IM (2004) Nuclear factor (NF)-kappaB proteins: therapeutic targets. Ann Rheum Dis 46:57–61Google Scholar
  19. 19.
    Kim Y, Fischer SM (1998) Transcriptional regulation of cyclooxygenase-2 in mouse skin carcinoma cells. Regulatory role of CCAAT/enhancer-binding proteins in the differential expression of cyclooxygenase-2 in normal and neoplastic tissues. J Biol Chem 273:27686–27694. doi: 10.1074/jbc.273.42.27686 CrossRefPubMedGoogle Scholar
  20. 20.
    Choi EK, Jang HC, Kim JH, Kang HC, Paek YW (2006) Enhancement of cytokine-mediated NF-kappa B activation by phosphatidylinositol 3-kinase inhibitors in monocytic cells. Int Immunopharmacol 6:908–915. doi: 10.1016/j.intimp.2006.01.007 CrossRefPubMedGoogle Scholar
  21. 21.
    Shukla Y, Taneja P (2002) Anticarcinogenic effect of black tea on pulmonary tumors in Swiss albino mice. Cancer Lett 176:137–141. doi: 10.1016/S0304-3835(01)00747-9 CrossRefPubMedGoogle Scholar
  22. 22.
    Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354. doi: 10.1073/pnas.76.9.4350 CrossRefPubMedGoogle Scholar
  23. 23.
    Arora A, Siddiqui A, Shukla Y (2004) Modulation of p53 in 7, 12 dimethylbenz[a]anthracene-induced skin tumors by diallyl sulfide in Swiss albino mice. Mol Cancer Ther 3:1459–1466PubMedGoogle Scholar
  24. 24.
    Lowry OH, Rosenbrough NK, Farr AL (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  25. 25.
    Weinstein IB (1991) Cancer prevention: recent progress and future opportunities. Cancer Res 51:5080s–5085sPubMedGoogle Scholar
  26. 26.
    DiGiovanni J (1992) Multistage carcinogenesis in mouse skin. Pharmacol Ther 54:63–128. doi: 10.1016/0163-7258(92)90051-Z CrossRefPubMedGoogle Scholar
  27. 27.
    AACR Chemoprevention Working Group (1999) Prevention of cancer in the next millennium: Report of the chemoprevention working group to the American Association for Cancer Research. Cancer Res 59:4743–4758Google Scholar
  28. 28.
    Swenberg JA, Hoel DG, Magee PN (1991) Mechanistic and statistical insight into the large carcinogenesis bioassays on N-nitrosodiethylamine and N-nitrosodimethylamine. Cancer Res 51:6409–6414PubMedGoogle Scholar
  29. 29.
    Banerjee S, Manna S, Saha P, Panda CK, Das S (2005) Black tea polyphenols suppress cell proliferation and induce apoptosis during benzo(a) pyrene-induced lung carcinogenesis. Eur J Cancer Prev 14:215–221. doi: 10.1097/00008469-200506000-00004 CrossRefPubMedGoogle Scholar
  30. 30.
    Sarmistha B, Sugata M, Sudeshna M, Debalina P, Chinmay KP, Sukta D (2006) Black Tea Polyphenols Restrict Benzopyrene-induced MouseLung Cancer Progression through Inhibition of Cox-2 and Induction of Caspase-3 Expression. Asian Pac J Cancer Prev 7:661–666Google Scholar
  31. 31.
    Xu Y, Ho CT, Amin SG, Han C, Chung FL (1992) Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res 52:3875–3879PubMedGoogle Scholar
  32. 32.
    Landau JM, Wang ZY, Yang GY, Ding W, Yang CS (1998) Inhibition of spontaneous formation of lung tumors and rhabdomyosarcomas in A/J mice by black and green tea. Carcinogenesis 19:501–507. doi: 10.1093/carcin/19.3.501 CrossRefPubMedGoogle Scholar
  33. 33.
    Cao J, Xu Y, Chen J, Klaunig JE (1996) Chemopreventive effects of green and black tea on pulmonary and hepatic carcinogenesis. Fundam Appl Toxicol 29:244–250. doi: 10.1006/faat.1996.0028 CrossRefPubMedGoogle Scholar
  34. 34.
    Shi ST, Wang ZY, Smith TJ, Hong JY, Chen WF, Ho CT, Yang CS (1994) Effects of green tea and black tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bioactivation, DNA methylation, and lung tumorigenesis in A/J mice. Cancer Res 54:4641–4647PubMedGoogle Scholar
  35. 35.
    Banerjee S, Panda CK, Das S (2006) Clove (Syzygium aromaticum L.), a potential chemopreventive agent for lung cancer. Carcinogenesis 27:1645–1654. doi: 10.1093/carcin/bgi372 CrossRefPubMedGoogle Scholar
  36. 36.
    Dohadwala M, Batra RK, Luo J, Lin Y, Krysan K, Pold M, Sharma S, Dubinett SM (2002) Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion. J Biol Chem 277:50828–50833. doi: 10.1074/jbc.M210707200 CrossRefPubMedGoogle Scholar
  37. 37.
    Krysan K, Dalwadi H, Sharma S, Põld M, Dubinett S (2004) COX-2-dependent stabilization of survivin in non-small cell lung cancer. FASEB J 18:206–208PubMedGoogle Scholar
  38. 38.
    Bennett A (1986) The production of prostonoids in human cancers and their implications for tumor progression. Prog Lipid Res 25:539–542. doi: 10.1016/0163-7827(86)90109-8 CrossRefPubMedGoogle Scholar
  39. 39.
    Karin M, Cao Y, Greten FR, Li ZW (2002) NF-kappaB in cancer: from innocent by stander to major culprit. Nat Rev Cancer 2:301–310. doi: 10.1038/nrc780 CrossRefPubMedGoogle Scholar
  40. 40.
    Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML, Mukhtar H (2003) Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. Oncogene 22:4851–4859. doi: 10.1038/sj.onc.1206708 CrossRefPubMedGoogle Scholar
  41. 41.
    Shishodia S, Aggarwal BB (2006) Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, I kappa B kinase activation and NF-kappa B-regulated gene expression. Oncogene 25:1463–1473. doi: 10.1038/sj.onc.1209194 CrossRefPubMedGoogle Scholar
  42. 42.
    Ciucci A, Gianferretti P, Piva R, Guyot T, Snape TJ, Roberts SM, Santoro MG (2006) Induction of apoptosis in estrogen receptor-negative breast cancer cells by natural and synthetic cyclopentenones: role of the IkappaB kinase/nuclear factor-kappaB pathway. Mol Pharmacol 70:1812–1821. doi: 10.1124/mol.106.025759 CrossRefPubMedGoogle Scholar
  43. 43.
    Nomura M, Ma W, Chen N, Bode AM, Dong Z (2000) Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced NF-kappaB activation by tea polyphenols, (-)-epigallocatechin gallate and theaflavins. Carcinogenesis 21:1885–1890. doi: 10.1093/carcin/21.10.1885 CrossRefPubMedGoogle Scholar
  44. 44.
    Siddiqui IA, Shukla Y, Adhami VM, Sarfaraz S, Asim M, Hafeez BB, Mukhtar H (2008) Suppression of NFkappaB and its regulated gene products by oral administration of green tea polyphenols in an autochthonous mouse prostate cancer model. Pharm Res 25:2135–2142. doi: 10.1007/s11095-008-9553-z CrossRefPubMedGoogle Scholar
  45. 45.
    Suganuma M, Sueika E, Sueoka N, Okabe S, Fujiki H (2000) Mechanisms of cancer prevention by tea polyphenols based on inhibition of TNF-alpha expression. Biofactors 13:67–72. doi: 10.1002/biof.5520130112 CrossRefPubMedGoogle Scholar
  46. 46.
    Nam S, Smith DM, Dou QP (2001) Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol Chem 276:13322–13330. doi: 10.1074/jbc.M004209200 CrossRefPubMedGoogle Scholar
  47. 47.
    Lin X, Bohle AS, Dohrmann P, Leuschner I, Schulz A, Kremer B, Fändrich F (2001) Overexpression of phosphatidylinositol 3-kinase in human lung cancer. Langenbecks Arch Surg 386:293–301. doi: 10.1007/s004230100203 CrossRefPubMedGoogle Scholar
  48. 48.
    Clarke RB (2003) p27KIP1 phosphorylation by PKB/Akt leads to poor breast cancer prognosis. Breast Cancer Res 5:162–163. doi: 10.1186/bcr596 CrossRefPubMedGoogle Scholar
  49. 49.
    Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17:590–603. doi: 10.1038/sj.leu.2402824 CrossRefPubMedGoogle Scholar
  50. 50.
    Romashkova JA, Makarov SS (1999) NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90CrossRefPubMedGoogle Scholar
  51. 51.
    Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269. doi: 10.1016/S0960-9822(06)00122-9 CrossRefPubMedGoogle Scholar
  52. 52.
    Chinni SR, Sarkar FH (2002) Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 8:1228–1236PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Preeti Roy
    • 1
  • Nidhi Nigam
    • 1
  • Madhulika Singh
    • 1
  • Jasmine George
    • 1
  • Smita Srivastava
    • 1
  • Hasnain Naqvi
    • 1
  • Yogeshwer Shukla
    • 1
  1. 1.Proteomics LaboratoryIndian Institute of Toxicology Research, (Council of Scientific & Industrial Research)M.G. Marg, LucknowIndia

Personalised recommendations