Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 4, pp 687–696 | Cite as

Induction of apoptosis by [6]-gingerol associated with the modulation of p53 and involvement of mitochondrial signaling pathway in B[a]P-induced mouse skin tumorigenesis

  • Nidhi Nigam
  • Jasmine George
  • Smita Srivastava
  • Preeti Roy
  • Kulpreet Bhui
  • Madhulika Singh
  • Yogeshwer ShuklaEmail author
Original Article



To unravel the molecular mechanisms underlying the chemopreventive potential of [6]-gingerol, a pungent ingredient of ginger rhizome (Zingiber officinale Roscoe, Zingiberaceae), against benzo[a]pyrene (B[a]P)-induced mouse skin tumorigenesis.


Topical treatment of [6]-gingerol (2.5 μM/animal) was given to the animals 30 min prior and post to B[a]P (5 μg/animal) for 32 weeks. At the end of the study period, the skin tumors/tissues were dissected out and examined histopathologically. Flow cytometry was employed for cell cycle analysis. Further immunohistochemical localization of p53 and regulation of related apoptogenic proteins were determined by Western blotting.


Chemopreventive properties of [6]-gingerol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Cell cycle analysis revealed that the appearance of sub-G1 peak was significantly elevated in [6]-gingerol treated animals with post treatment showing higher efficacy in preventing tumorigenesis induced by B[a]P. Moreover, elevated apoptotic propensity was observed in tumor tissues than the corresponding non-tumor tissues. Western blot analysis also showed the same pattern of chemoprevention with [6]-gingerol treatment increasing the B[a]P suppressed p53 levels, also evident by immunohistochemistry, and Bax while decreasing the expression of Bcl-2 and Survivin. Further, [6]-gingerol treatment resulted in release of Cytochrome c, Caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction.


On the basis of the results we conclude that [6]-gingerol possesses apoptotic potential in mouse skin tumors as mechanism of chemoprevention hence deserves further investigation.


Mouse skin tumorigenesis [6]-Gingerol Benzo(a)pyrene Chemoprevention Apoptosis 



Authors are thankful to Director Indian Institute of Toxicology Research, Lucknow (Council of Scientific & Industrial Research, India) for his keen interest in the study. We are thankful to Dr. Neeraj Mathur, Scientist for statistically analyzing the data. Authors are also thankful to Department of Biotechnology (India) and Council of Scientific & Industrial Research, New Delhi (under NWP-17) for jointly funding this work.


  1. 1.
    Greenlee RT, Hill-Harmon MB, Murray T, Thun M (2001) Cancer statistics. CA Cancer J Clin 51:15–36CrossRefPubMedGoogle Scholar
  2. 2.
    Gupta S, Mukhtar H (2001) Chemoprevention of skin cancer through natural agents. Skin Pharmacol Appl Skin Physiol 14:373–385PubMedGoogle Scholar
  3. 3.
    Jemal A, Siegel R, Ward E, Murray T et al (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66CrossRefPubMedGoogle Scholar
  4. 4.
    Bowden GT (2004) Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signaling. Nat Rev Cancer 4:23–35CrossRefPubMedGoogle Scholar
  5. 5.
    Nair MK, Varghese C, Mahadevan S, Cherian T, Joseph F (1998) Cutaneous malignant melanoma—clinical epidemiology and survival. J Indian Med Assoc 96:19–20PubMedGoogle Scholar
  6. 6.
    Takata M, Saida T (2005) Early cancers of the skin: clinical, histopathological, and molecular characteristics. Int J Clin Oncol 10:391–397CrossRefPubMedGoogle Scholar
  7. 7.
    Afzal M, Al-Hadidi D, Menon M, Pesek J, Dhami MS (2001) Ginger: an ethnomedical, chemical and pharmacological review. Drug Metabol Drug Interact 18:159–190PubMedGoogle Scholar
  8. 8.
    Katiyar SK, Agarwal R, Mukhtar H (1996) Inhibition of tumor promotion in SENCAR mouse skin by ethanol extract of Zingiber officinale rhizome. Cancer Res 56:1023–1030PubMedGoogle Scholar
  9. 9.
    Park KK, Chun KS, Lee JM, Lee SS, Surh YJ (1998) Inhibitory effects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett 129:139–144CrossRefPubMedGoogle Scholar
  10. 10.
    Kim SO, Chun KS, Kundu JK, Surh YJ (2004) Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NFκB and p38 MAPK in mouse skin. Biofactors 21:27–31CrossRefPubMedGoogle Scholar
  11. 11.
    Kim JK, Kim Y, Na KM, Surh YJ, Kim TY (2007) [6]-Gingerol prevents UVB-induced ROS production and COX-2 expression in vitro and in vivo. Free Radic Res 41:603–614CrossRefPubMedGoogle Scholar
  12. 12.
    Singh A, Shukla Y (1998) Antitumour activity of diallyl sulfide on polycyclic aromatic hydrocarbon-induced mouse skin carcinogenesis. Cancer Lett 131:209–214CrossRefPubMedGoogle Scholar
  13. 13.
    Bode AM, Ma WY, Surh YJ, Dong Z (2001) Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol. Cancer Res 61:850–853PubMedGoogle Scholar
  14. 14.
    Bogovaski P (1979) Tumours of skin. In: Turusov VS (ed) Pathology of tumours in laboratory animals, vol II, Tumours of the mouse, IARC scientific publication no. 23. IARC, LyonGoogle Scholar
  15. 15.
    Arora A, Siddiqui IA, 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
  16. 16.
    Arora A, Shukla Y (2002) Induction of apoptosis by diallyl sulfide in DMBA-induced mouse skin tumors. Nutr Cancer 44:89–94CrossRefPubMedGoogle Scholar
  17. 17.
    Siddiqui IA, Adhami VM, Afaq F, Ahmad N, Mukhtar H (2004) Modulation of phosphatidylinositol-3-kinase/protein kinase B- and mitogen-activated protein kinase-pathways by tea polyphenols in human prostate cancer cells. J Cell Biochem 91:232–242CrossRefPubMedGoogle Scholar
  18. 18.
    Lowry OH, Rosenbrough NK, Farr AL (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  19. 19.
    Agarwal ML, Taylor WR, Chernov MV, Chernova OB, Stark GR (1998) The p53 network. J Biol Chem 273:1–4CrossRefPubMedGoogle Scholar
  20. 20.
    Mowat MR (1998) p53 in tumor progression: life, death and everything. Adv Cancer Res 74:25–48CrossRefPubMedGoogle Scholar
  21. 21.
    Burns PA, Kemp CJ, Gannon JV, Lane DP, Bremmer R, Balmain A (1991) A Loss of heterozygosity and mutational alterations of the p53 gene in skin tumors of interspecific hybrid mice. Oncogene 6:2363–2369PubMedGoogle Scholar
  22. 22.
    Schuler M, Green DR (2001) Mechanisms of p53-dependent apoptosis. Biochem Soc Trans 29:684–688CrossRefPubMedGoogle Scholar
  23. 23.
    Safe S, Wargovich MJ, Lamartiniere CA, Mukhtar H (1999) Symposium on mechanisms of action of naturally occurring anticarcinogens. Toxicol Sci 52:1–8Google Scholar
  24. 24.
    Lamson DW, Brignall MS (2001) Natural agents in the prevention of cancer, part two: preclinical data and chemoprevention for common cancers. Altern Med Rev 6:167–187PubMedGoogle Scholar
  25. 25.
    Lee SH, Cekanova M, Baek SJ (2008) Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Mol Carcinog 47:197–208CrossRefPubMedGoogle Scholar
  26. 26.
    Yagihashi S, Miura Y, Yagasaki K (2008) Inhibitory effect of gingerol on the proliferation and invasion of hepatoma cells in culture. Cytotechnology 57:129–136CrossRefPubMedGoogle Scholar
  27. 27.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  28. 28.
    Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancake P, Moll UM (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11:577–590CrossRefPubMedGoogle Scholar
  29. 29.
    Harn HJ, Ho LI, Liu CA, Liu GC (1996) Down regulation of bcl-2 by p53 in nasopharyngeal carcinoma and lack of detection of its specific t (14;18) chromosomal translocation in fixed tissues. Histopathol 28:317–323CrossRefGoogle Scholar
  30. 30.
    Hockenbery DM, Giedt CD, O’Neill JW, Manion MK (2002) Mitochondria and apoptosis: new therapeutic targets. Adv Cancer Res 85:203–242CrossRefPubMedGoogle Scholar
  31. 31.
    MacCarthy-Morrogh L, Mouzakiti A, Townsend P, Brimmell M (1999) Bcl-2-related proteins and cancer. Biochem Soc Trans 27:785–789PubMedGoogle Scholar
  32. 32.
    Salomons GS, Brady HJ, Verwijs-Janssen M, Van Den Berg JD (1997) The Bax:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. Int J Cancer 71:959–965CrossRefPubMedGoogle Scholar
  33. 33.
    Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16PubMedGoogle Scholar
  34. 34.
    Bursztajn S, Feng JJ, Berman SA, Nanda AR (2000) Poly (ADP-ribose) polymerase induction is an early signal of apoptosis in human neuroblastoma. Brain Res Mol Brain Res 76:363–376CrossRefPubMedGoogle Scholar
  35. 35.
    Kolthur-Seetharam U, Dantzer F, McBurney MW, de Murcia G, Sassone-Corsi P (2006) Control of AIF mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell cycle 5:873–877PubMedGoogle Scholar
  36. 36.
    Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22:8581–8589CrossRefPubMedGoogle Scholar
  37. 37.
    Deveraux QL, Reed JC (1999) IAP family proteins—suppressors of apoptosis. Genes Dev 13:239–252CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Nidhi Nigam
    • 1
  • Jasmine George
    • 1
  • Smita Srivastava
    • 1
  • Preeti Roy
    • 1
  • Kulpreet Bhui
    • 1
  • Madhulika Singh
    • 1
  • Yogeshwer Shukla
    • 1
    Email author
  1. 1.Proteomics LaboratoryIndian Institute of Toxicology Research (CSIR)LucknowIndia

Personalised recommendations