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Effects of resveratrol in combination with 5-fluorouracil on N-methylnitrosourea-induced colon cancer in rats

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Abstract

5-Fluorouracil (5-FU) is the most commonly used therapy and the conventional treatment for colorectal cancer. However, its toxicity to normal tissues is considered a major obstacle to successful cancer chemotherapy; thus, resveratrol is used in combination with 5-FU to reduce its toxicity. The goal of our study is to investigate the mechanisms underlying the effects of resveratrol alone and in combination with 5-FU in inhibiting experimentally induced colon cancer. Rats were divided into eight groups including control, resveratrol, 5-FU, resveratrol with 5FU, N-methylnitrosourea, treated group 1, 2, and 3 groups. Oxidant/antioxidant parameters, plasma NF-κB, and real-time PCR quantification of colonic P53 gene expression were assessed. Histopathological and immunohistochemistry of cyclooxygenases (COX-1, COX-2) were also performed. The data showed that N-methylnitrosourea significantly increased colon malondialdehyde (MDA), advanced oxidation protein products (AOPP), and nuclear factor-κB (NF-κB) concomitant with a reduction in superoxide dismutase (SOD) and a downregulation in P53 gene expression. Supplementation with resveratrol improved these values in treated groups. Thus, resveratrol is a highly promising antioxidant, anti-cancer, and anti-inflammatory compound through activating antioxidant defense system, its direct scavenging activity, as well as its biological activities through downregulation of COX-2 via suppression of NF-κB activation.

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References

  • Abdallah IZA, Khattab HAH, Heeba GH (2011) Gastroprotective effect of Cordia myxa L. fruit extract against indomethacin-induced gastric ulceration in. RatsLife Sci J 8(3):433–445

    Google Scholar 

  • Asao T, Takayuki A, Shibata HR, Batist G, Brodt P (1992) Eradication of hepatic metastases of carcinoma H-59 combination chemoimmunotherapy with liposomal muramyltripeptide, 5-fluorouracil and leucovorin. Cancer Res 52:6254–6257

    CAS  PubMed  Google Scholar 

  • Bio-Rad Laboratories Inc (2006) Real-time PCR obesity: evidence and mechanisms. Nutr. Rev., applications guide. Bulletin 5279:101

    Google Scholar 

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

    CAS  Google Scholar 

  • Cersosimo RJ (2013) Management of advanced colorectal cancer, part 1. Am J Health Syst Pharm 70(5):395–406

    CAS  PubMed  Google Scholar 

  • Chang CT, Ho TY, Lin H, Liang JA, Huang HC et al (2012) 5-Fluorouracil induced intestinal mucositis via nuclear factor-kB activation by transcriptomic analysis and in vivo bioluminescence imaging. PLoS One 7(3):e31808

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chung SS, Dutta P, Austin D, Wang P, Awad A, Vadgama JV (2018) Combination of resveratrol and 5-fluorouracil enhanced anti-telomerase activity and apoptosis by inhibiting STAT3 and Akt signaling pathways in human colorectal cancer cells. Oncotarget 9(68):32943–32957. https://doi.org/10.18632/oncotarget25993 eCollection 2018 Aug 31

    Article  PubMed  PubMed Central  Google Scholar 

  • Culling CFA (1974) Handbook of histopathological and histochemical techniques, 3rd edn. Butterworth and Company, London, pp 126–159

    Google Scholar 

  • Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE, Barnes PJ (2004) Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 287:L774–L783

    CAS  PubMed  Google Scholar 

  • Eshak MG, Ghaly IS, Khalil WKB, Farag IM, Ghanem KZ (2010) Genetic alterations induced by toxic effect of thermally oxidized oil and protective role of tomatoes and carrots in mice. J Am Sci 6(4):175–188

    Google Scholar 

  • Fremont L (2000) Biological effects of resveratrol. Life Sci 66:663–673

    CAS  PubMed  Google Scholar 

  • Frombaum M, Clanche SL, Bonnefont-Rousselot D, Borderie D (2012) Antioxidant effects of resveratrol and other stilbene derivatives on oxidative stress and ·NO bioavailability: potential benefits to cardiovascular diseases. Biochimie 94:269–276

    CAS  PubMed  Google Scholar 

  • Harrison S, Benziger H (2011) The molecular biology of colorectal carcinoma and its implications: a review. Surgeon 9(4):200–210

    PubMed  Google Scholar 

  • Hussein J, El-Khayat Z, Farrag A, Medhat D, Abdel Latif Y, Oraby F (2014) Inhibition of hyperhomocysteinemia in indomethacin induced peptic ulcer: impact of pomegranate juice supplementation. J Chem Pharm Res 6(10):131–138

    Google Scholar 

  • Hussein J, Refaat E, Medhat D, El-Bana M, Abdel Latif Y, Farrag A, Nazeef N, Moify M (2016) Panax ginseng attenuates experimental brain injury by increasing brain derived neurotrophic factor and inhibition of neuro-inflammation. J Chem Pharm Res 8(1):186–195

    CAS  Google Scholar 

  • Issa JP (2008) Colon cancer: it’s CIN or CIMP. Clin Cancer Res 14:5939–5940

    PubMed  Google Scholar 

  • Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220

    CAS  PubMed  Google Scholar 

  • Karin M (1999) The beginning of the end: IκB kinase (IKK) and NF-κB activation. J Biol Chem 274:27339–27342

    CAS  PubMed  Google Scholar 

  • Leonard SS, Xia C, Jiang BH, Stinefelt B, Klandorf H, Harris GK, Shi X (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun 309:1017–1026

    CAS  PubMed  Google Scholar 

  • Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338

    CAS  PubMed  Google Scholar 

  • Lopez-Velez M, Martinez-Martinez F, Del Valle-Ribes C (2003) The study of phenolic compounds as natural antioxidants in wine. Crit Rev Food Sci Nutr 43:233–244

    CAS  PubMed  Google Scholar 

  • Meng Y, Ma Q-Y, Kou X-P, Xu J (2005) Effect of resveratrol on activation of nuclear factor kappa-B and inflammatory factors in rat model of acute pancreatitis. World J Gastroenterol 11(4):525–528

    CAS  PubMed  PubMed Central  Google Scholar 

  • Narisawa T, Fukaura Y (2003) Prevention by intrarectal 5-aminosalicylic acid of N-methylnitrosourea-induced colon cancer in F344 rats. Dis Colon Rectum 46(7):900–903

    PubMed  Google Scholar 

  • Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K et al (2009) Results of a phase I pilot clinical trial examining the effect of plant derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res 1:25–37

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nishikimi M, Roa NA, Yogi K (1972) Measurement of superoxide dismutase. Biochem Biophys Res Commun 46:849–854

    CAS  PubMed  Google Scholar 

  • Patel KR, Brown VA, Jones DJ, Britton RG, Hemingway D et al (2010) Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res 70:7392–7399

    CAS  PubMed  PubMed Central  Google Scholar 

  • Patton C, Crouch S (1977) Spectrophotometric and kinetic investigation of the berthelot reaction for the determination pf ammonia. J Anal Chem 49:464–469

    CAS  Google Scholar 

  • Pervaiz S (2003) Resveratrol: from grapevines to mammalian biology. FASEB J 17:1975–1985

    CAS  PubMed  Google Scholar 

  • Raftery L, Goldberg RM (2010) Optimal delivery of cytotoxic chemotherapy for colon cancer. Cancer J 16(3):214–219

    CAS  PubMed  Google Scholar 

  • Reitman S, Frankel S (1957) A colorimetric method for the determination of serum glutamic oxaloacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28(1):56–63

    CAS  Google Scholar 

  • Rivera H, Shibayama M, Tsutsumi V, Perez-Alvarez V, Muriel P (2008) Resveratrol and trimethylated resveratrol protect from acute liver damage induced by CCl4 in the rat. J Appl Toxicol 28:147–155

    CAS  PubMed  Google Scholar 

  • Sato A, Okada M, Shibuya K, Watanabe E, Seino S, Suzuki K, Narita Y, Shibui S, Kayama T, Kitanaka C (2013) Resveratrol promotes proteasome-dependent degradation of Nanog via p53 activation and induces differentiation of glioma stem cells. Stem Cell Res 11:601–610

    CAS  PubMed  Google Scholar 

  • Schmatz R, Perreira LB, Stefanello N, Mazzanti C, Spanevello R, Gutierres J, Bagatini M, Martins CC, Abdalla FH, da Silva Serres JD, Zanini D, Vieira JM, Cardoso AM, Schetinger MR, Morsch VM (2012) Effects of resveratrol on biomarkers of oxidative stress and on the activity of delta aminolevulinic acid dehydratase in liver and kidney of streptozotocin-induced diabetic rats. Biochimie 94:374–383

    CAS  PubMed  Google Scholar 

  • Sharma SH, Kumara JS, Chellappan DR, Nagarajan S (2018) Molecular chemoprevention by morin—a plant flavonoid that targets nuclear factor kappa B in experimental colon cancer. Biomed Pharmacother 100:367–373

    CAS  PubMed  Google Scholar 

  • Siemann EH, Creasy LL (1992) Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic 43:49–52

    CAS  Google Scholar 

  • Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69:145–182

    CAS  PubMed  Google Scholar 

  • Soliman RH, Ismail OA, Badr MS, Nasr SM (2017) Resveratrol ameliorates oxidative stress and organ dysfunction in Schistosoma mansoni infected mice. Exp Parasitol 174:52–58

    CAS  PubMed  Google Scholar 

  • Takaoka MJ (1940) The phenolic substances of white hellebore (Veratrum grandiflorum Loes. fil.). J Facult Sci Hokkaido Imp Univ 3:1–16

    CAS  Google Scholar 

  • Tornatore L, Thotakura AK, Bennett J, Moretti M, Franzoso G (2012) The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol 22(11):557–566

    CAS  PubMed  Google Scholar 

  • Uchiyamara M, Mihara M (1978) Determination of malondialdehyde in tissue by thiobarbituric acid test. Anal Biochem 86:271–278

    Google Scholar 

  • Van den Heuvel SJ, Van Laar T, Kast WM, Melief CJ, Zantema A, Van der Eb AJ (1990) Association between the cellular p53 and the adenovirus 5 E1B-55kd proteins reduces the oncogenicity of Ad-transformed cells. EMBO J 9:2621–2629

    PubMed  PubMed Central  Google Scholar 

  • Violette S, Laurent Poulain L, Dussaulx E, Pepin D, Faussat AM, Chambaz J, Lacorte JM, Staedel C, Lesuffleur T (2002) Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-XL in addition to Bax and p53 status. Int J Cancer 98:498–504

    CAS  PubMed  Google Scholar 

  • Voboril R, Hochwald SN, Li J, Brank A, Weberova J, Wessels F, Moldawer LL, Camp ER, MacKay SLD (2004) Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer. J Surg Res 120:178–188

    CAS  PubMed  Google Scholar 

  • Wolter F, Ulrich S, Stein J (2004) Molecular mechanisms of the chemopreventive effects of resveratrol and its analogs in colorectal cancer: key role of polyamines? J Nutr 134:3219–3222

    CAS  PubMed  Google Scholar 

  • Worthley DL, Leggett BA (2010) Colorectal cancer: molecular features and clinical opportunities. Clin Biochem Rev 31:31–38

    PubMed  PubMed Central  Google Scholar 

  • Wu SL, Sun ZJ, Yu L, Meng KW, Qin XL, Pan CE (2004) Effect of resveratrol and in combination with 5-FU on murine liver cancer. World J Gastroenterol 10(20):3048–3052

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yar AS, Menevse Alp SE (2011) The effects of resveratrol on cyclooxygenase-1 and -2, nuclear factor kappa beta, matrix metalloproteinase-9, and sirtuin 1 mRNA expression in hearts of streptozotocin-induced diabetic rats. Genet Mol Res 10(4):2962–2975

    CAS  PubMed  Google Scholar 

  • Yazbeck R, Lindsay R, Catherine AA, Benkendorff K, Gordon SH (2015) Combined effects of muricid extract and 5-fluorouracil on intestinal toxicity in rats. Evid Based Complement Alternat Med 2015, Article ID 170858:1–9

    Google Scholar 

  • Young DS (2001) Effect of disease on clinical laboratory test, 4th edn. AACC

  • Zordoky BN, Robertson IM, Dyck JR (2015) Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta 1852:1155–1177

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors acknowledge the National Research Centre (NRC), Giza, Egypt, for providing necessary facilities for accomplishment of this research work.

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Authors and Affiliations

  1. Medical Biochemistry Department, National Research Center, 33 El Behouth St., Giza, Dokki, 12622, Egypt

    Yasmin Abdel Latif, Mona El-Bana, Jihan Hussein & Zakaria El-Khayat

  2. Pathology Department, National Research Centre, Giza, Dokki, Egypt

    Abdel Razik Farrag

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  1. Yasmin Abdel Latif
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  2. Mona El-Bana
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  4. Zakaria El-Khayat
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Correspondence to Yasmin Abdel Latif.

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Prior ethical clearance for experimentation was approved by the National Research Centre (NRC), Giza, Egypt. In all the experimentation, the ethical care and treatment of the animals were conducted as per the guidelines laid down and following the regulations of the ethical committee of NRC.

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Abdel Latif, Y., El-Bana, M., Hussein, J. et al. Effects of resveratrol in combination with 5-fluorouracil on N-methylnitrosourea-induced colon cancer in rats. Comp Clin Pathol 28, 1351–1362 (2019). https://doi.org/10.1007/s00580-019-02967-2

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