RETRACTED ARTICLE: Chemopreventive Potential of Resveratrol in Mouse Skin Tumors Through Regulation of Mitochondrial and PI3K/AKT Signaling Pathways

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To investigate the chemopreventive potential of resveratrol, a phytoalexin found in seeds and skin of grapes, berries and peanuts in 7,12 dimethyl benz(a)anthracene (DMBA) induced mouse skin tumorigenesis.


Topical treatment of resveratrol was given to the animals 1 h prior to DMBA for 28 weeks. At the end of the study period, the skin tumors were dissected out and western blotting was carried out to examine the regulation of proteins involved in anti-tumorigenesis in response to resveratrol.


Chemopreventive properties of resveratrol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Results of the western blotting showed that resveratrol treatment increased the DMBA suppressed p53 and Bax while decreased the expression of Bcl-2 and Survivin. Further, resveratrol supplementation resulted in release of cytochrome C, caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction. Resveratrol was also found to inhibit skin tumorigenesis through regulation of Phosphatidylinositol-3-kinase (PI3K)/ and AKT proteins which are implicated in cancer progression because it stimulates proliferation and suppresses apoptosis.


Based on the results we can conclude that resveratrol regulates apoptosis and cell survival in mouse skin tumors as mechanism of chemoprevention hence deserve to be a chemopreventive agent.

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Change history


  1. 1.

    D. R. Bickers, and M. Athar. Novel approaches to chemoprevention of skin cancer. J. Dermatol. 27:691–695 (2000).

    CAS  PubMed  Google Scholar 

  2. 2.

    L. Fremont. Biological effects of resveratrol. Life Sci. 66:663–673 (2000). doi:10.1016/S0024-3205(99)00410-5.

    CAS  PubMed  Google Scholar 

  3. 3.

    D. K. Das, M. Sato, P. S. Ray, G. Maulik, R. M. Engleman, A. A. Bertelli, and A. Bertelli. Cardio protection of red wine: role of polyphenolic antioxidants. Drugs Exp. Clin. Res. 25:115–120 (1999).

    CAS  PubMed  Google Scholar 

  4. 4.

    U. R. Pendurthi, F. Meng, N. Mackman, and L.V. Rao. Mechanism of resveratrol mediated suppression of tissue factor gene expression. Thromb. Haemost. 87:155–162 (2002).

    CAS  PubMed  Google Scholar 

  5. 5.

    S. Banerjee, C. Bueso-Ramos, and B.B. Aggarwal. Suppression of 7, 12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor—Kappa B, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 62:4945–4954 (2002).

    CAS  Google Scholar 

  6. 6.

    M. Jang, L. Cai, O. G. Udeani, K. V. Slowing, C. F. Thomas, C. W. W. Beecher, H. H. S. Fong, N. R. Farnsworth, A. D. Kinghorn, R. G. Mehta, R. C. Moon, and J. M. Pezzuto. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 275:218–220 (1997). doi:10.1126/science.275.5297.218.

    CAS  PubMed  Google Scholar 

  7. 7.

    M. V. Clement, J. L. Hirpara, and S. Pervaiz. Chemopreventive agent resveratrol, a natural product derived from grapes triggers Cd95 signalling-dependent apoptosis in human tumor cells. Blood. 92:996–1002 (1998).

    CAS  PubMed  Google Scholar 

  8. 8.

    Y. J. Surh, Y. J. Hurh, J. Y. Kang, E. Lee, G. Kong, and S. J. Lee. Resveratrol,an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells. Cancer Lett. 140:1–10 (1999). doi:10.1016/S0304-3835(99)00039-7.

    CAS  PubMed  Google Scholar 

  9. 9.

    Q. B. She, A. M. Bode, W. Y. Ma, N. Y. Chen, and Z. Dong. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res. 61:1604–1610 (2001).

    CAS  PubMed  Google Scholar 

  10. 10.

    N. Ahmad, V. M. Adhami, F. Afaq, D. K. Feyes, and H. Mukhtar. Reveratrol causes WAF-1/p21-mediated G1-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin. Cancer Res. 7:1466–1473 (2001).

    CAS  PubMed  Google Scholar 

  11. 11.

    R. Joseph, and B. Alfanso. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. 98:10983–10985 (2001). doi:10.1073/pnas.211430998.

    Google Scholar 

  12. 12.

    N. Kalra, P. Roy, S. Prasad, and Y. Shukla. Resveratrol induces apoptosis involving mitochondrial pathways in mouse skin tumorigenesis. Life Sci. 82:348–358 (2008). doi:10.1016/j.lfs.2007.11.006.

    CAS  PubMed  Google Scholar 

  13. 13.

    A. Singh, and Y. Shukla. Anti tumor activity of diallyl sulphide on polycyclic aromatic hydrocarbon-induced mouse skin carcinogenesis. Cancer Lett. 131:209–214 (1998). doi:10.1016/S0304-3835(98)00152-9.

    CAS  PubMed  Google Scholar 

  14. 14.

    I. A. Siddiqui, V. M. Adhami, F. Afaq, N. Ahmad, and H. Mukhtar. 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. 91:232–242 (2004). doi:10.1002/jcb.10737.

    CAS  PubMed  Google Scholar 

  15. 15.

    D. Johnson, and H. Lardy. In R. W. Estabrook, and M. E. Pullman (eds.), Methods in Enzymology, Oxidation and Phosphorylation, Vol. X, Academic, New York, 1967, pp. 94–96.

    Google Scholar 

  16. 16.

    A. Arora, I. A. Siddiqui, and Y. Shukla. Modulation of p53 in 7,12-dimethylbenz[a] benzanthracene-induced skin tumors by diallyl sulphide in Swiss albino mice. Mol. Cancer Ther. 11:1459–1466 (2004).

    Google Scholar 

  17. 17.

    O. H. Lowry, N. K. Rosenbrough, and A. L. Farr. Protein measurement with folin phenol reagent. J. Biol. Chem. 193:265–275 (1951).

    CAS  PubMed  Google Scholar 

  18. 18.

    S. W. Lowe, H. E. Ruley, T. Jacks, and D. E. Housman. p53-dependent apoptosis modulates the cytotoxicity of anticancer drugs. Cell. 74:957–967 (1993). doi:10.1016/0092-8674(93)90719-7.

    CAS  PubMed  Google Scholar 

  19. 19.

    A. R. Clarke, S. Gledhill, M. L. Hooper, C. C. Bird, and A. H. Wyllie. p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. Oncogene. 9:1767–1773 (1994).

    CAS  PubMed  Google Scholar 

  20. 20.

    G. J. Kapadia, M. A. Azuine, H. Tokuda, M. Takasaki, T. Mukainaka, T. Konoshima, and H. Nishino. Chemopreventive effectof resveratrol, sesamol, sesame oil and sunflower oil in the Epstein-barr virus early antigen activation assay and the mouse skin two stage carcinogenesis. Pharmacol. Res. 45:499–505 (2002). doi:10.1006/phrs.2002.0992.

    CAS  PubMed  Google Scholar 

  21. 21.

    V. M. Adhami, F. Afaq, and N. Ahmad. Involvement of the Retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) Cells. Biochem. Biophys. Res. Commun. 288:579–585 (2001). doi:10.1006/bbrc.2001.5819.

    CAS  PubMed  Google Scholar 

  22. 22.

    G. J. Soleas, L. Grass, P. D. Josephy, D. M. Goldberg, and E. P. Diamandis. A comparison of the anticarcinogenic properties of four red wine polyphenols. Clin. Biochem. 35:119–124 (2002). doi:10.1016/S0009-9120(02)00275-8.

    CAS  PubMed  Google Scholar 

  23. 23.

    Z. D. Fu, Y. Cao, K. F. Wang, S. F. Xu, and R. Han. Chemopreventive effect of resveratrol to cancer. Ai Zheng. 23:869–873 (2004).

    CAS  PubMed  Google Scholar 

  24. 24.

    J. F Kerr, A. H. Wyllie, and A. R. Currie. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer. 26:239–257 (1972).

    Google Scholar 

  25. 25.

    M. Mihara, S. Erster, A. Zaika, O. Petrenko, T. Chittenden, P. Pancake, and U. M. Moll. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell. 11:77–590 (2003). doi:10.1016/S1097-2765(03)00050-9.

    Google Scholar 

  26. 26.

    H. J. Harn, L. I. Ho, C. A. Liu, and G. C. Liu. 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. Histopathology. 28:317–323 (1996). doi:10.1046/j.1365-2559.1996.d01-431.x.

    CAS  PubMed  Google Scholar 

  27. 27.

    D. M. Hockenbery, C. D. Giedt, J. W. O’Neill, and M. K. Manion. Mitochondria and apoptosis: new therapeutic targets. Adv. Cancer Res. 85:203–242 (2002). doi:10.1016/S0065-230X(02)85007-2.

    CAS  PubMed  Google Scholar 

  28. 28.

    L. MacCarthy-Morrogh, A. Mouzakiti, P. Townsend, and M. Brimmell. Bcl-2-related proteins and cancer. Biochem. Soc. Trans. 27:785–789 (1999).

    CAS  PubMed  Google Scholar 

  29. 29.

    G. S. Salomons, H. J. Brady, M. Verwijs-Janssen, and J. D. Van Den Berg. The Bax:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia. Int. J. Cancer. 71:959–965 (1997). doi:10.1002/(SICI)1097-0215(19970611)71:6<959::AID-IJC9>3.0.CO;2-X.

    CAS  PubMed  Google Scholar 

  30. 30.

    G. M. Cohen. Caspases: the executioners of apoptosis. Biochem. J. 326:1–16 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    S. Bursztajn, J. J. Feng, S. A. Berman, and A. R. Nanda. Poly (ADP-ribose) polymerase induction is an early signal of apoptosis in human neuroblastoma. Brain Res. Mol. Brain Res. 76:363–376 (2000). doi:10.1016/S0169-328X(00)00026-7.

    CAS  PubMed  Google Scholar 

  32. 32.

    U. Kolthur-Seetharam, F. Dantzer, M. W. McBurney, G. de Murcia, and P. Sassone-Corsi. Control of AIF mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell cycle. 5:873–877 (2006).

    CAS  PubMed  Google Scholar 

  33. 33.

    D. C. Altieri. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 22:8581–8589 (2003). doi:10.1038/sj.onc.1207113.

    CAS  PubMed  Google Scholar 

  34. 34.

    Q. L. Deveraux, and J. C. Reed. IAP family proteins—suppressors of apoptosis. Genes Dev. 13:239–252 (1999). doi:10.1101/gad.13.3.239.

    CAS  Google Scholar 

  35. 35.

    M. Castedo, J. L. Perfettini, T. Roumier, K. Andreau, R. Medema, and G. Kroemer. Cell death by mitotic catastrophe: a molecular definition. Oncogene. 23:2825–2837 (2004). doi:10.1038/sj.onc.1207528.

    CAS  PubMed  Google Scholar 

  36. 36.

    B. B. Aggarwal, A. Bhardwaj, R. S. Aggarwal, N. P. Seeram, S. Shishodia, and Y. Takada. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical trials. Anticancer Res. 24:2783–2840 (2004).

    CAS  PubMed  Google Scholar 

  37. 37.

    T. O. Chan, S. E. Rittenhouse, and P. N. Tsichlis. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu. Rev. Biochem. 68:965–1041 (1999). doi:10.1146/annurev.biochem.68.1.965.

    CAS  PubMed  Google Scholar 

  38. 38.

    R. Srivastava, A. Ratheesh, R. K. Gude, K. V. Rao, D. Panda, and G. Subrahmanyam. Resveratrol inhibits type II phosphatidylinositol turnover. Biochem. Pharmacol. 70:1048–1045 (2005). doi:10.1016/j.bcp.2005.07.003.

    CAS  PubMed  Google Scholar 

  39. 39.

    T. M. Poolman, L. L. Ng, P. B. Farmer, and M. M. Manson. Inhibition of the respiratory burst by resveratrol in human monocytes: correlation with inhibition of PI3K signalling. Free Radic. Biol. Med. 39:118–132 (2005). doi:10.1016/j.freeradbiomed.2005.02.036.

    CAS  PubMed  Google Scholar 

  40. 40.

    O. Rachid, and M. Alkhalaf. Resveratrol regulation of PI3K-AKT signaling pathway genes in MDA-MB-231 breast cancer cells. Cancer Genomics Proteomic. 3:383–388 (2006).

    CAS  Google Scholar 

  41. 41.

    Y. Lu, H. Wang, and G. B. Mills. Targeting PI3K-AKT pathway for cancer therapy. Rev. Clin. Exp. Hematol. 7:205–228 (2003).

    CAS  PubMed  Google Scholar 

  42. 42.

    L. Asnaghi, A. Calastretti, A. Bevilacqua, I. D’Agnano, G. Gatti, G. Canti, D. Delia, S. Capaccioli, and A. Nicolin. Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene. 23:5781–5791 (2004). doi:10.1038/sj.onc.1207698.

    CAS  PubMed  Google Scholar 

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Authors are thankful to Dr. Ashwani Kumar, Director Indian Institute of Toxicology Research, (Council for Scientific & Industrial Research, India) for his keen interest in the study. Authors are also thankful to Department of Biotechnology (India) for providing fellowship to Ms. Preeti Roy and Indian Council of Medical Research (India) for providing fellowship to Ms. Neetu Kalra and Mr. Sahdeo Prasad.

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Correspondence to Yogeshwer Shukla.

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Roy, P., Kalra, N., Prasad, S. et al. RETRACTED ARTICLE: Chemopreventive Potential of Resveratrol in Mouse Skin Tumors Through Regulation of Mitochondrial and PI3K/AKT Signaling Pathways. Pharm Res 26, 211–217 (2009).

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  • apoptosis
  • chemoprevention
  • mouse skin tumorigenesis
  • PI3K/AKT pathway
  • resveratrol