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Regulatory effects of resveratrol on antioxidant enzymes: A mechanism of growth inhibition and apoptosis induction in cancer cells

  • Research Article
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Molecules and Cells

An Erratum to this article was published on 26 March 2013

Abstract

Resveratrol (RSV) is a natural polyphenol that is known as a powerful chemopreventive and chemotherapeutic anticancer molecule. This study focused on the effects of RSV on the activities and expression levels of antioxidant enzymes in the cancer cells. Prostate cancer PC-3 cells, hepatic cancer HepG2 cells, breast cancer MCF-7 cells and the non-cancerous HEK293T kidney epithelial cells were treated with a wide range of RSV concentrations (10-100 μM) for 24–72 h. Cell growth was estimated by trypan blue staining, activities of the antioxidant enzymes were measured spectrophotometrically, expression levels of the antioxidant enzymes were quantified by digitalizing the protein band intensities on Western blots, and the percentage of apoptotic cells was determined by flow cytometry. Treatment with a low concentration of RSV (25 μM) significantly increased superoxide dismutase (SOD) activity in PC-3, HepG2 and MCF-7 cells, but not in HEK293T cells. Catalase (CAT) activity was increased in HepG2 cells, but no effect was found on glutathione peroxidase (GPX) upon RSV treatment. RSV-induced SOD2 expression was observed in cancer cells, although the expression of SOD1, CAT and GPX1 was unaffected. Apoptosis increased upon RSV treatment of cancer cells, especially in PC-3 and HepG2 cells. Together, our data demonstrated that RSV inhibits cancer cell growth with minimal effects on non-cancerous cells. We postulate that the disproportional up-regulation of SOD, CAT and GPX expression and enzymatic activity in cancer cells results in the mitochondrial accumulation of H2O2, which in turn induces cancer cell apoptosis.

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References

  • Arsova-Sarafinovska, Z., Eken, A., Matevska, N., Erdem, O., Sayal, A., Savaser, A., Banev, S., Petrovski, D., Dzikova, S., Georgiev, V., et al. (2009). Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer. Clin. Biochem. 42, 1228–1235.

    Article  PubMed  CAS  Google Scholar 

  • Bae, S., Lee, E.M., Cha, H.J., Kim, K., Yoon, Y., Lee, H., Kim, J., Kim, Y.J., Lee, H.G., Jeung, H.K., et al. (2011). Resveratrol alters microRNA expression profiles in A549 human non-small cell lung cancer cells. Mol. Cells 32, 243–249.

    Article  PubMed  CAS  Google Scholar 

  • Benitez, D.A., Pozo-Guisado, E., Alvarez-Barrientos, A., Fernandez-Salguero, P.M., and Castellón, E.A. (2007). Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. J. Androl. 28, 282–293.

    Article  PubMed  CAS  Google Scholar 

  • Bishayee, A. (2009). Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev. Res. (Phila) 2, 409–418.

    Article  CAS  Google Scholar 

  • Bradford, M.M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248–254.

    Article  PubMed  CAS  Google Scholar 

  • Carbó, N., Costelli, P., Baccino, F.M., López-Soriano, F.J., and Argilés, J.M. (1999). Resveratrol, a natural product present in wine, decreases tumour growth in a rat tumour model. Biochem. Biophys. Res. Commun. 254, 739–743.

    Article  PubMed  Google Scholar 

  • Chen, Y., Tseng, S.H., Lai, H.S., and Chen, W.J. (2004). Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery 136, 57–66.

    Article  PubMed  Google Scholar 

  • Chung-man Ho, J., Zheng, S., Comhair, S.A., Farver, C., and Erzurum, S.C. (2001). Differential expression of manganese superoxide dismutase and catalase in lung cancer. Cancer Res. 61, 8578–8585.

    PubMed  CAS  Google Scholar 

  • De Craemer, D., Pauwels, M., Hautekeete, M., and Roels, F. (1993). Alterations of hepatocellular peroxisomes in patients with cancer. Catalase cytochemistry and morphometry. Cancer 71, 3851–3858.

    Article  PubMed  Google Scholar 

  • Elchuri, S., Oberley, T.D., Qi, W., Eisenstein, R.S., Jackson Roberts, L., Van Remmen, H., Epstein, C.J., and Huang, T.T. (2005). CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367–380.

    Article  PubMed  CAS  Google Scholar 

  • Frémont, L., Belguendouz, L., and Delpal, S. (1999). Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. Life Sci. 64, 2511–2521.

    Article  PubMed  Google Scholar 

  • Giorgio, M., Migliaccio, E., Orsini, F., Paolucci, D., Moroni, M., Contursi, C., Pelliccia, G., Luzi, L., Minucci, S., Marcaccio, M., et al. (2005). Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122, 221–233.

    Article  PubMed  CAS  Google Scholar 

  • Giorgio, M., Trinei, M., Migliaccio, E., and Pelicci, P.G. (2007). Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat. Rev. Mol. Cell Biol. 8, 722–728.

    Article  CAS  Google Scholar 

  • Góth, L. (1991). A simple method for determination of serum catalase activity and revision of reference range. Clin. Chim. Acta 196, 143–151.

    Article  PubMed  Google Scholar 

  • Graf, E., and Penniston, J.T. (1980). Method for determination of hydrogen peroxide, with its application illustrated by glucose assay. Clin. Chem. 26, 658–660.

    PubMed  CAS  Google Scholar 

  • Harikumar, K.B., and Aggarwal, B.B. (2008). Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 7, 1020–1035.

    Article  PubMed  CAS  Google Scholar 

  • Huang, X., and Zhu, H.L. (2011). Resveratrol and its analogues: promising antitumor agents. Anticancer Agents Med. Chem. 11, 479–490.

    Article  PubMed  Google Scholar 

  • Jang, M., Cai, L., Udeani, G.O., Slowing, K.V., Thomas, C.F., Beecher, C.W., Fong, H.H., Farnsworth, N.R., Kinghorn, A.D., Mehta, R.G., et al. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218–220.

    Article  PubMed  CAS  Google Scholar 

  • Jeon, S.H., Jae-Hoon Park, J.H., and Chang, S.G. (2007). Expression of antioxidant enzymes (catalase, superoxide dis-mutase, and glutathione peroxidase) in human bladder cancer. Korean J. Urol. 48, 921–926.

    Article  Google Scholar 

  • Kasapović, J., Pejić, S., Todorović, A., Stojiljković, V., and Pajović, S.B. (2008). Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages. Cell Biochem. Funct. 26, 723–730.

    Article  PubMed  Google Scholar 

  • Khan, M.A., Tania, M., Zhang, D.Z., and Chen, H.C. (2010). Antioxidant enzymes and cancer. Chin. J. Cancer Res. 22, 87–92.

    Article  CAS  Google Scholar 

  • Klaunig, J.E., and Kamendulis, L.M. (2004). The role of oxidative stress in carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 44, 239–267.

    Article  PubMed  CAS  Google Scholar 

  • Kovacic, P., and Somanathan, R. (2010). Multifaceted approach to resveratrol bioactivity: focus on antioxidant action, cell signaling and safety. Oxid. Med. Cell Longev. 3, 86–100.

    Article  PubMed  Google Scholar 

  • Kowaltowski, A.J., Castilho, R.F., and Vercesi, A.E. (2001). Mitochondrial permeability transition and oxidative stress. FEBS Lett. 495, 12–15.

    Article  PubMed  CAS  Google Scholar 

  • Miller, N.J., and Rice-Evans, C.A. (1995). Antioxidant activity of resveratrol in red wine. Clin. Chem. 41, 1789.

    PubMed  CAS  Google Scholar 

  • Mo, W., Xu, X., Xu, L., Wang, F., Ke, A., Wang, X., and Guo, C. (2012). Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 11, 601–609.

    Article  Google Scholar 

  • Muqbil, I., Beck, F.W., Bao, B., Sarkar, F.H., Mohammad, R.M., Hadi, S.M., and Azmi, A.S. (2012). Old wine in a new bottle: the Warburg effect and anticancer mechanisms of resveratrol. Curr. Pharm. Des. 18, 1645–1654.

    Article  PubMed  CAS  Google Scholar 

  • Nakata, R., Takahashi, S., and Inoue, H. (2012). Recent advances in the study on resveratrol. Biol. Pharm. Bull. 35, 273–279.

    Article  PubMed  CAS  Google Scholar 

  • Park, C.E., Yun, H., Lee, E.B., Min, B.I., Bae, H., Choe, W., Kang, I., Kim, S.S., and Ha, J. (2010). The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. J. Med. Food 13, 815–820.

    Article  PubMed  CAS  Google Scholar 

  • Park, S.J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A.L., et al. (2012). Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148, 421–433.

    Article  PubMed  CAS  Google Scholar 

  • Patel, K.R., Scott, E., Brown, V.A., Gescher, A.J., Steward, W.P., and Brown, K. (2011). Clinical trials of resveratrol. Ann. N. Y. Acad. Sci. 1215, 161–169.

    Article  PubMed  CAS  Google Scholar 

  • Petit, E., Courtin, A., Kloosterboer, H.J., Rostène, W., Forgez, P., and Gompel, A. (2009). Progestins induce catalase activities in breast cancer cells through PRB isoform: correlation with cell growth inhibition. J. Steroid Biochem. Mol. Biol. 115, 153–160.

    Article  PubMed  CAS  Google Scholar 

  • Robb, E.L., Page, M.M., Wiens, B.E., and Stuart, J.A. (2008). Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD. Biochem. Biophys. Res. Commun. 367, 406–412.

    Article  PubMed  CAS  Google Scholar 

  • Rotruck, J.T., Pope, A.L., Ganther, H.E., Swanson, A.B., Hafeman, D.G., and Hoekstra, W.G. (1973). Selenium: biochemical role as a component of glutathione peroxidase. Science 179, 588–590.

    Article  PubMed  CAS  Google Scholar 

  • Scarlatti, F., Maffei, R., Beau, I., Codogno, P., and Ghidoni, R. (2008). Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ. 15, 1318–1329.

    Article  PubMed  CAS  Google Scholar 

  • Scott, E., Steward, W.P., Gescher, A.J., and Brown, K. (2012). Resveratrol in human cancer chemoprevention—choosing the ‘right’ dose. Mol. Nutr. Food Res. 56, 7–13.

    Article  PubMed  CAS  Google Scholar 

  • Sengottuvelan, M., Deeptha, K., and Nalini, N. (2009). Resveratrol ameliorates DNA damage, prooxidant and antioxidant imbalance in 1,2-dimethylhydrazine induced rat colon carcinogenesis. Chem. Biol. Interact. 181, 193–201.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, A., Tripathi, M., Satyam, A., and Kumar, L. (2009). Study of antioxidant levels in patients with multiple myeloma. Leuk. Lymphoma 50, 809–815.

    Article  PubMed  CAS  Google Scholar 

  • Sun, Y.I., Oberley, L.W., and Li, Y. (1988). A simple method for clinical assay of superoxide dismutase. Clin. Chem. 34, 497–500.

    PubMed  CAS  Google Scholar 

  • Yu, J., and Kim, A.K. (2009). Effect of taurine on antioxidant enzyme system in B16F10 melanoma cells. Adv. Exp. Med. Biol. 643, 491–499.

    Article  PubMed  CAS  Google Scholar 

  • Zhou, H.B., Chen, J.J., Wang, W.X., Cai, J.T., and Du, Q. (2005). Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice. World J. Gastroenterol. 11, 280–284.

    PubMed  CAS  Google Scholar 

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Correspondence to Han-chun Chen.

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Khan, M.A., Chen, Hc., Wan, Xx. et al. Regulatory effects of resveratrol on antioxidant enzymes: A mechanism of growth inhibition and apoptosis induction in cancer cells. Mol Cells 35, 219–225 (2013). https://doi.org/10.1007/s10059-013-2259-z

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  • DOI: https://doi.org/10.1007/s10059-013-2259-z

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