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http://dx.doi.org/10.22034/APJCP.2016.17.11.4991

Quercetin Confers Tumoricidal Activity Through Multipathway Mechanisms in A N-Methylnitrosourea Rat Model of Colon Cancer  

Ahmed, Hanaa H (Hormones Department, National Research Centre)
Aglan, Hadeer A (Hormones Department, National Research Centre)
Zaazaa, Asmaa M (Zoology Department, Faculty of Women for Arts, Science and Education, Ain Shams University)
Shalby, Aziza B (Hormones Department, National Research Centre)
Toumy, Sayed A El (Chemistry of Tannins Department, National Research Centre)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.17, no.11, 2016 , pp. 4991-4998 More about this Journal
Abstract
Objective: This research was conducted to explore mechanisms behind the potency of quercetin in inhibiting colon cancer induced in an experimental model. Materials and Methods: Forty adult male rats of Wistar strain were distributed into 4 groups; a negative control group, a colon cancer bearing group, a quercetin-treated group and a 5-fluorouracil (5-FU)-treated group. Serum TAG72 and GAL3 levels were quantified by ELISA. Colonic Wnt5a and Axin-1 gene expression was estimated by PCR. In addition, colonic tissues were subjected to immunohistochemical examination of Bax expression and histological investigation of histopathological alterations. Results: Quercetin elicited significant reduction in serum TAG72 and GAL3 levels, in addition to significant suppression of colonic Wnt5a gene expression and amplification of colonic Axin-1 gene expression. Also, it caused moderate positive reaction for Bax in mucosal epithelium. Conclusion: The present research provides experimental evidence about the activity of quercetin in the colon cancer of rats. Inhibitory effects on cancer development might be ascribable to regulatory action on Wnt signaling and induction of apoptosis.
Keywords
Colon cancer; quercetin; 5-fluorouracil; Wnt signaling; rats;
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1 Balaji C, Muthukumaran J, Nalini N (2014). Chemopreventive effect of sinapic acid on 1,2-dimethylhydrazineinduced experimental rat colon carcinogenesis. Hum Exp Toxicol, 33, 1253-68.   DOI
2 Banchroft JD, Stevens A, Turner DR (1996). Theory and practice of histological techniques. 4thEd. Churchill Livingstone, Philadelphia, USA pp 25-90.
3 Bancroft JD, Gamble M (2008). Theory and practice of histological techniques. 6th Ed. Churchill Livingstone, Philadelphia, USA pp 433-69.
4 Agullo G, Gamet L, Besson C, Demigne C, Remesy C (1994). Quercetin exerts a preferential cytotoxic effect on active dividing colon carcinoma HT29 and CaCO2 cells. Cancer Lett, 87, 55-63.   DOI
5 Ahmed H, Banerjee PP, Vasta GR (2007). Differential expression of galectins in normal, benign and malignant prostate epithelial cells: silencing of galectin-3 expression in prostate cancer by its promoter methylation. Biochem Biophys Res Commun, 358, 241-6.   DOI
6 Barker N, Clevers H (2006). Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov, 5, 997-1014.   DOI
7 Bulzomi P, Galluzzo P, Bolli A, et al (2012). The pro-apoptotic effect of quercetin in cancer cell lines requires $ER{\beta}$-dependent signals. J Cell Physiol, 227, 1891-8.   DOI
8 Cappell MS (2007). From colonic polyps to colon cancer: pathophysiology, clinical presentation, screening and colonoscopic therapy. Minerva Gastroenterol Dietol, 53, 351-73.
9 Chao DT, Korsmeyer SJ (1998). BCL-2 family: regulators of cell death. Annu Rev Immunol, 16, 395-419.   DOI
10 Chen W, Lin M, Zhang B, et al (2007). Survey of molecular profiling during human colon cancer development and progression by immunohistochemical staining on tissue microarray. World J Gastroenterol, 13, 699-708.   DOI
11 Raftery L, Goldberg RM (2010). Optimal delivery of cytotoxic chemotherapy for colon cancer. Cancer J, 16, 214-9.   DOI
12 Kikuchi A (1999). Roles of Axin in the Wnt signalling pathway. Cell Signal, 11, 777-88.   DOI
13 Kim HP, Son KH, Chang HW, Kang SS (2004). Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci, 96, 229-45.   DOI
14 Park C, Chang JY, Hahm ER, et al (2005). Quercetin, a potent inhibitor against ${\beta}$-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun, 328, 227-34.   DOI
15 Paul S, Kundu R (2013). Antiproliferative activity of methanolic extracts from two green algae, Enteromorpha intestinalis and Rizoclonium riparium on HeLa cells. DARU, 21, 1-12.   DOI
16 Chien AJ, Moon RT (2007). WNTs and WNT receptors as therapeutic tools and targets in human disease processes. Front Biosci, 12, 448-57.   DOI
17 Clements WM, Lowy AM, Groden J (2003). Adenomatous polyposis coli/beta-catenin interaction and downstream targets: altered gene expression in gastrointestinal tumors. Clin Colorectal Cancer, 3, 113-20.   DOI
18 Pinson KI, Brennan J, Monkley S, Avery BJ, Skarnes WC (2000). An LDL-receptor-related protein mediates Wnt signalling in mice. Nature, 407, 535-8.   DOI
19 Plaumann B, Fritsche M, Rimpler H, Brandner G, Hess RD (1996). Flavonoids activate wild type p53. Oncogene, 13, 1605-14.
20 Puglisi F, Minisini AM, Barbone F, et al (2004). Galectin-3 expression in non-small cell lung carcinoma. Cancer Lett, 212, 233-9.   DOI
21 Rajamanickam S, Agarwal R (2008). Natural products and colon cancer: current status and future prospects. Drug Dev Res, 69, 460-71.   DOI
22 Ousingsawat J, Spitzner M, Puntheeranurak S, et al (2007). Expression of voltage-gated potassium channels in human and mouse colonic carcinoma. Clin Cancer Res, 13, 824-31.   DOI
23 Ramos S (2008). Cancer chemoprevention and chemotherapy, dietary polyphenols and signalling pathways. Mol Nutr Food Res, 52, 507-52.   DOI
24 Rampone B, Schiavone B, Martino A, Confuorto G (2010). Current role of hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis from colorectal cancer. World J Gastroenterol, 16, 1299-1302.   DOI
25 Reya T, Clevers H (2005). Wnt signalling in stem cells and cancer. Nature, 434, 843-50.   DOI
26 Duthie GG, Duthie SJ, Kyle JA (2000). Plant polyphenols in cancer and heart disease: implications as nutritional antioxidants. Nutr Res Rev, 13, 79-106.   DOI
27 Clevers H (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127, 469-80.   DOI
28 Csokay B, Pradja N, Weber G, Olah E (1997). Molecular mechanisms in the antiproliferative action of quercetin. Life Sci, 60, 2157-63.   DOI
29 Damdinsuren B, Nagano H, Wada H, et al (2007). Interferon alpha receptors are important for antiproliferative effect of interferon-alpha against human hepatocellular carcinoma cells. Hepatol Res, 37, 77- 83.   DOI
30 Eguchi H, Nagano H, Yamamoto H, et al (2000). Augmentation of antitumor activity of 5-fluorouracil by interferon alpha is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells. Clin Cancer Res, 6, 2881-90.
31 Cheong T, Shin J, Chun K (2010). Silencing of galectin-3 changes the gene expression and augments the sensitivity of gastric cancer cells to chemotherapeutic agents. Cancer Sci, 101, 94-102.   DOI
32 Endo H, Hosono K, Fujisawa T, et al (2009). Involvement of JNK pathway in the promotion of the early stage of colorectal carcinogenesis under high-fat dietary conditions. Gut, 58, 1637-43.   DOI
33 Endo K, Kohnoe S, Tsujita E, et al (2005). Galectin-3 expression is a potent prognostic marker in colorectal cancer. Anticancer Res, 25, 3117-21.
34 Greco C, Vona R, Cosimelli M, et al (2004). Cell surface overexpression of galectin-3 and the presence of its ligand 90k in the blood plasma as determinants in colon neoplastic lesions. Glycobiology, 14, 783-92.   DOI
35 Nagano H, Miyamoto A, Wada H, et al (2007). Interferon-alpha and 5-fluorouracil combination therapy after palliative hepatic resection in patients with advanced hepatocellular carcinoma, portal venous tumor thrombus in the major trunk, and multiple nodules. Cancer, 110, 2493-501.   DOI
36 Nakahara S, Raz A (2007). Regulation of cancer-related gene expression by galectin-3 and the molecular mechanism of its nuclear import pathway. Cancer Metastasis Rev, 26, 605-10.   DOI
37 Nakamura M, Nagano H, Sakon M, et al (2007). Role of the Fas/FasL pathway in combination therapy with interferon-alpha and fluorouracil against hepatocellular carcinoma in vitro. J Hepatol, 46, 77-88.   DOI
38 Galluzzo P, Martini C, Bulzomi P, et al (2009). Quercetin induced apoptotic cascade in cancer cells: Antioxidant versus estrogen receptor a dependent mechanisms. Mol Nutr Food Res, 53, 699-708.   DOI
39 Gellad ZF, Provenzale D (2010). Colorectal cancer: national and international perspective on the burden of disease and public health impact. Gastroenterology, 138, 2177-90.   DOI
40 Guadagni F, Roselli M, Cosimelli M, et al (1996). TAG-72 expression and its role in the biological evaluation of human colorectal cancer. Anticancer Res, 16, 2141-8.
41 Harborne JB (1984). Phytochemical methods. 2nd Ed, Chapman and Hall, London pp 1-36.
42 He XT, Fan XM, Zha XL (2011). Ghrelin inhibits 5-fluorouracil- induced apoptosis in colonic cancer cells. J Gastroenterol Hepatol, 26, 1169-73.   DOI
43 Hughes RC (2001). Galectins as modulators of cell adhesion. Biochimie, 83, 667-76.   DOI
44 Iurisci I, Tinari N, Natoli C, et al (2000). Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res, 6, 1389-93.
45 Katoh M (2003). Expression and regulation of WNT1 in human cancer: up-regulation of WNT1 by beta-estradiol in MCF-7 cells. Int J Oncol, 22, 209-12.
46 Kondo M, Nagano H, Wada H, et al (2005). Combination of IFN-alpha and 5-fluorouracil induces apoptosis through IFN-alpha/beta receptor in human hepatocellular carcinoma cells. Clin Cancer Res, 11, 1277-86.
47 Kim JY, Kim EH, Park SS, et al (2008). Quercetin sensitizes human hepatoma cells to TRAIL-induced apoptosis via Sp1-mediated DR5 up-regulation and proteasome-mediated c-FLIPS down-regulation. J Cell Biochem, 105, 1386-98.   DOI
48 Kiss R, Dubois J (2011). Quercetin inhibits a large panel of kinases implicated in cancer cell biology. Int J Oncol, 38, 833-42.
49 Klaus A, Birchmeier W (2008). Wnt signalling and its impact on development and cancer. Nat Rev Cancer, 8, 387-98.   DOI
50 Kuo PC, Liu HF, Chao JI (2004). Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. J Biol Chem, 279, 55875-985.   DOI
51 Noda T, Nagano H, Takemasa L, et al (2009). Activation of Wnt/b-catenin signalling pathway induces chemoresistance to interferon-a/5-fluorouracil combination therapy for hepatocellular carcinoma. Br J Cancer, 100, 1647-58.   DOI
52 Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW (1999). p53/p21 WAF1/CIP1 expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells. Cancer Lett, 136, 215-21.   DOI
53 Narisawa T, Fukaura Y (2003). Prevention by intrarectal 5-aminosalicylic acid of N-methylnitrosourea-induced colon cancer in F344 rats. Dis Colon Rectum, 46, 900-3.   DOI
54 Nguyen TT, Tran E, Nguyen TH, et al (2004). The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis, 25, 647-59.
55 Mense SM, Hei TK, Ganju RK, Bhat HK (2008). Phytoestrogens and breast cancer prevention: Possible mechanisms of action. Environ Health Perspect, 116, 426-33.   DOI
56 Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW (1997). Serine phosphorylation-regulated biquitination and degradation of beta-catenin. J Biol Chem, 272, 24735-8.   DOI
57 Mabry TJ, Markham KR, Thomas MB (1970). The Systematic identification of flavonoids, Springer, Verlag and New York pp 35-109.
58 Lee JS, Ishimoto A, Yanagawa S (1999). Characterization of mouse disheveled (Dvl) proteins in Wnt/Wingless signaling pathway. J Biol Chem, 274, 21464-70.   DOI
59 Logan CY, Nusse R (2004). The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 20, 781-810.   DOI
60 Lu H, Peng T, Hu X, et al (2015). Quercetin potentiates the effect of ${\gamma}{\delta}$ T cells via modulating the expressions of Granzyme B, perforin and IFN-$\gamma$ and also regulates the Wnt/${\beta}$-catenin signalling pathway in human colon cancer cells. Bangladesh J Pharmacol, 10, 251-9.   DOI
61 Markham KR (1982). Techniques of flavonoid identification, Academic Press, London pp 1-113.
62 Uddin S, Choudhry MA (1995). Quercetin, a bioflavonoid, inhibits the DNA synthesis of human leukemia cells. Biochem Mol Biol Int, 36, 545-50.
63 Sadik NA, Shaker OG (2013). Inhibitory effect of a standardized pomegranate fruit extract onwnt signalling in 1,2-dimethylhydrazine induced rat colon carcinogenesis. Dig Dis Sci, 58, 2507-17.   DOI
64 Song L, Tang JW, Owusu L, et al (2014). Galectin-3 in cancer. Clin Chim Acta, 431, 185-91.   DOI
65 Steinberg P (2010). The role of inflammation in colon cancer induced by food contaminants. Toxicology Lett, 196, 5-6.
66 Stevenson DE, Hurst RD (2007). Polyphenolic phytochemicals-just antioxidants or much more?. Cell Mol Life Sci, 64, 2900-16.   DOI
67 Stoner GD (2009). Foodstuffs for preventing cancer: the preclinical and clinical development of berries. Cancer Prev Res, 2, 187-94.   DOI
68 van Duijnhoven FJ, Bueno-De-Mesquita HB, Ferrari P, et al (2009). Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr, 89, 1441-52.   DOI
69 Vijayababu MR, Arunkumar A, Kanagaraj P, et al (2006). Quercetin downregulates matrix metalloproteinases 2 and 9 proteins expression in prostate cancer cells (PC-3). Mol Cell Biochem, 287, 109-16.   DOI
70 Wada H, Nagano H, Yamamoto H, et al (2007). Combination therapy of interferon alpha and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins. Oncol Rep, 18, 801-9.
71 Scambia G, Panici PB, Ranelletti FO, et al (1994). Quercetin enhances transforming growth factor beta 1 secretion by human ovarian cancer cells. Int J Cancer, 57, 211-5.   DOI
72 Yamamoto T, Nagano H, Sakon M, et al (2004). Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferonalpha/5-fluorouracil against Hepatocellular Carcinoma. Clin Cancer Res, 10, 7884-95.   DOI
73 Zamin LL, Filippi-Chiela EC, Vargas J, et al (2014). Quercetin promotes glioma growth in a rat model. Food Chem Toxicol, 63, 205-11.   DOI
74 Zhang N, Ding YQ, Liang L (2006). Association of galectin-3 expression with biological behaviors of human colorectal carcinoma. Nanfang Yikedaxue Xuebao, 26, 1685-9.
75 Zheng Z, Cheng K, Chao J, Wu J, Wang M (2008). Tyrosinase inhibitors from Paper Mulberry (Broussonetia Papyrifera). Food Chem, 106, 529-35.   DOI
76 Zou J, Glinsky VV, Landon LA, Matthews L, Deutscher SL (2005). Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion. Carcinogenesis, 26, 309-18.
77 Seeram NP (2008). Berry fruits for cancer prevention: current status and future prospects. J Agric Food Chem, 55, 630-5.
78 Bafico A, Liu G, Goldin L, Harris V, Aaronson SA (2004). An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell, 6, 497-506.   DOI
79 Ahmed HH, Shousha WGh, El-Mezayen HA, El-Toumy SA, Ramadan AR (2015): Updates on the biochemical and molecular mechanisms of N-nitrosodiethylamine-induced hepatocellular carcinoma: promising therapeutic role of Punica granatum peel extract. Int J Pharm Sci Rev Res, 32, 121-44.
80 Asao T, Takayuki A, Shibata HR, Batist G, Brodt P (1992). Eradication of hepatic metastases of carcinoma H-59 combination chemoimmunotherapy with liposomal muramyl tripeptide, 5-fluorouracil, and leucovorin. Cancer Res, 52, 6254-7.