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Published in: Journal of Experimental & Clinical Cancer Research 1/2009

Open Access 01-12-2009 | Research

Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences

Authors: AlaaEddeen M Seufi, Safinz S Ibrahim, Tarek K Elmaghraby, Elsayed E Hafez

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2009

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Abstract

Background

The incidence of hepatocellular carcinoma is increasing in many countries. The estimated number of new cases annually is over 500,000, and the yearly incidence comprises between 2.5 and 7% of patients with liver cirrhosis. The incidence varies between different geographic areas, being higher in developing areas; males are predominantly affected, with a 2:3 male/female ratio

Methods

Experiments were designed to examine the effect of N-Nitrosodiethylamine (NDEA) as cancer-inducer compound and to confirm the preventive effect of the flavonoid quercetin on hepatocellular carcinoma in rats. Briefly, thirty six male albino rats of Wistar strain were divided into 3 groups: the 1st group was administered NDEA alone (NDEA-treated), the 2nd group was treated simultaneously with NDEA and quercetin (NDEA+Q) and the 3rd group was used as control (CON). Randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) as well as p53-specifi PCR assays were employed to determine genomic difference between treated, and control animals. Histological confirmation as well as oxidant/antioxidant status of the liver tissue was done.

Results

RAPD analysis of liver samples generated 8 monomorphic bands and 22 polymorphic bands in a total of 30-banded RAPD patterns. Cluster analysis and statistical analyses of RAPD data resulted in grouping control and NDEA+Q samples in the same group with 80% similarity cut-off value. NDEA-treated samples were clustered in a separate group. Specific PCR assay for polymorphism of P53 gene revealed a uniform pattern of allele separation in both control and NDEA+Q samples. Quercetin anticancer effect was exhibited in significant decrease of oxidative stress and significant decrease of antioxidant activity. Histopathological studies showed normal liver histology of the NDEA+Q samples. Meanwhile, several cancer-induced features were clearly observable in NDEA-treated samples.

Conclusion

This paper demonstrated that preventive effect of quercetin on hepatocarcinoma in rats by RAPD-PCR, tracing the effect on p53 gene and by histopathological evidence. Hereby, it was proved that quercetin exerted its preventive effect via decreased oxidative stress and decreased antioxidant activity.
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Literature
1.
go back to reference Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA: Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci. 2002, 963: 13-20.CrossRef Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA: Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci. 2002, 963: 13-20.CrossRef
2.
go back to reference MacPhee DG: Time-dependent mutagenesis and cancer: a new role for antimutagenesis in cancer prevention?. Mutat Res. 1998, 402: 29-39.CrossRef MacPhee DG: Time-dependent mutagenesis and cancer: a new role for antimutagenesis in cancer prevention?. Mutat Res. 1998, 402: 29-39.CrossRef
3.
go back to reference Butterworth BE, Bogdanffy MS: A comprehensive approach for integration of toxicity and cancer risk assessment. Regul Toxicol Pharmacol. 1999, 29: 23-36. 10.1006/rtph.1998.1273.CrossRef Butterworth BE, Bogdanffy MS: A comprehensive approach for integration of toxicity and cancer risk assessment. Regul Toxicol Pharmacol. 1999, 29: 23-36. 10.1006/rtph.1998.1273.CrossRef
4.
go back to reference Lijinsky W: Chemistry and Biology of N-Nitroso Compounds. 1992, Cambridge University Press, Cambridge, England Lijinsky W: Chemistry and Biology of N-Nitroso Compounds. 1992, Cambridge University Press, Cambridge, England
5.
go back to reference Tricker AR, Preussmann R: Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential. Mutat Res. 1991, 259: 277-289. 10.1016/0165-1218(91)90123-4.CrossRef Tricker AR, Preussmann R: Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential. Mutat Res. 1991, 259: 277-289. 10.1016/0165-1218(91)90123-4.CrossRef
6.
go back to reference Sander J: Kann nitrit in der menschlichen nahrung ursache einer kerbsentstehung durch nitrosaminbildung sein?. Arch Hyg Bakteriol. 1967, 151: 22-28. Sander J: Kann nitrit in der menschlichen nahrung ursache einer kerbsentstehung durch nitrosaminbildung sein?. Arch Hyg Bakteriol. 1967, 151: 22-28.
7.
go back to reference Bogovski P, Bogovski S: Animal species in which N-nitroso compounds induce cancer. Int J Cancer. 1981, 27: 471-474. 10.1002/ijc.2910270408.CrossRef Bogovski P, Bogovski S: Animal species in which N-nitroso compounds induce cancer. Int J Cancer. 1981, 27: 471-474. 10.1002/ijc.2910270408.CrossRef
8.
go back to reference Andrzejewski P, Kasprzyk-hordern B, Nawrocki J: N-nitrosomethylethylamine (nmea) and n-nitrosodiethylamine (ndea), two new potential disinfection byproducts; formation during water disinfection with chlorine. Global NEST Journal. 2005, 7: 17-26. Andrzejewski P, Kasprzyk-hordern B, Nawrocki J: N-nitrosomethylethylamine (nmea) and n-nitrosodiethylamine (ndea), two new potential disinfection byproducts; formation during water disinfection with chlorine. Global NEST Journal. 2005, 7: 17-26.
9.
go back to reference Di Carlo G, Mascolo N, Izzo AA, Capasso F: Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci. 1999, 65: 337-353. 10.1016/S0024-3205(99)00120-4.CrossRef Di Carlo G, Mascolo N, Izzo AA, Capasso F: Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci. 1999, 65: 337-353. 10.1016/S0024-3205(99)00120-4.CrossRef
10.
go back to reference Choi JA, Kim JY, Lee JY, Kang CM, Kwon HJ, Yoo YD, Kim TW, Lee YS, Lee SJ: Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol. 2001, 19: 837-844. Choi JA, Kim JY, Lee JY, Kang CM, Kwon HJ, Yoo YD, Kim TW, Lee YS, Lee SJ: Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol. 2001, 19: 837-844.
11.
go back to reference Ong CS, Tran E, Nguyen TT, Ong CK, Lee SK, Lee JJ, Ng CP, Leong C, Huynh H: Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Oncol Rep. 2004, 11: 727-733. Ong CS, Tran E, Nguyen TT, Ong CK, Lee SK, Lee JJ, Ng CP, Leong C, Huynh H: Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Oncol Rep. 2004, 11: 727-733.
12.
go back to reference Beniston RG, Campo MS: Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1. Oncogene. 2003, 22: 5504-5514. 10.1038/sj.onc.1206848.CrossRef Beniston RG, Campo MS: Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1. Oncogene. 2003, 22: 5504-5514. 10.1038/sj.onc.1206848.CrossRef
13.
go back to reference Gupta K, Panda D: Perturbation of microtubule polymerization by quercetin through tubulin binding: a novel mechanism of its antiproliferative activity. Biochemistry. 2002, 41: 13029-13038. 10.1021/bi025952r.CrossRef Gupta K, Panda D: Perturbation of microtubule polymerization by quercetin through tubulin binding: a novel mechanism of its antiproliferative activity. Biochemistry. 2002, 41: 13029-13038. 10.1021/bi025952r.CrossRef
14.
go back to reference Yoshizumi M, Tsuchiya K, Kirima K, Kyaw M, Suzaki Y, Tamaki T: Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells. Mol Pharmacol. 2001, 60: 656-665. Yoshizumi M, Tsuchiya K, Kirima K, Kyaw M, Suzaki Y, Tamaki T: Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells. Mol Pharmacol. 2001, 60: 656-665.
15.
go back to reference Li W, Cagle PT, Botero RC, Liang JJ, Zhang Z, Tan D: Significance of overexpression of alpha methylacyl-coenzyme A racemase in hepatocellular carcinoma. J Exp Clinic Cancer Res. 2008, 27: 2-10.1186/1756-9966-27-2.CrossRef Li W, Cagle PT, Botero RC, Liang JJ, Zhang Z, Tan D: Significance of overexpression of alpha methylacyl-coenzyme A racemase in hepatocellular carcinoma. J Exp Clinic Cancer Res. 2008, 27: 2-10.1186/1756-9966-27-2.CrossRef
16.
go back to reference Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H: Trends in oxidative aging theories. Free Radic Biol Med. 2007, 43: 477-503. 10.1016/j.freeradbiomed.2007.03.034.CrossRef Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H: Trends in oxidative aging theories. Free Radic Biol Med. 2007, 43: 477-503. 10.1016/j.freeradbiomed.2007.03.034.CrossRef
17.
go back to reference Champe , et al: Biochemistry. 2008, Lippincott Williams and Wilkins, Fourth Champe , et al: Biochemistry. 2008, Lippincott Williams and Wilkins, Fourth
18.
go back to reference Meister A: Glutathione metabolism and its selective modification. J Biol Chem. 1988, 263: 17205-8. Meister A: Glutathione metabolism and its selective modification. J Biol Chem. 1988, 263: 17205-8.
19.
go back to reference Mannervik B: The enzymes of glutathione metabolism: an overview. Biochem Soc Trans. 1987, 15: 717-8.CrossRef Mannervik B: The enzymes of glutathione metabolism: an overview. Biochem Soc Trans. 1987, 15: 717-8.CrossRef
20.
go back to reference Yoshioka T, Kawada K, Shunada T, Mori M: Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol. 1979, 135: 372-376. Yoshioka T, Kawada K, Shunada T, Mori M: Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am J Obstet Gynecol. 1979, 135: 372-376.
21.
go back to reference Srivastava SK, Beutler E: Accurate measurement of oxidized glutathione content of human, rabbit, and rat red blood cells and tissues. Anal Biochem. 1968, 25: 70-76. 10.1016/0003-2697(68)90082-1.CrossRef Srivastava SK, Beutler E: Accurate measurement of oxidized glutathione content of human, rabbit, and rat red blood cells and tissues. Anal Biochem. 1968, 25: 70-76. 10.1016/0003-2697(68)90082-1.CrossRef
22.
go back to reference Arthur JR, Boyne R: Superoxide dismutase and glutathione peroxidase activities in neutrophils from selenium deficient and copper deficient cattle. Life Sci. 1985, 36 (16): 1569-1575. 10.1016/0024-3205(85)90381-9.CrossRef Arthur JR, Boyne R: Superoxide dismutase and glutathione peroxidase activities in neutrophils from selenium deficient and copper deficient cattle. Life Sci. 1985, 36 (16): 1569-1575. 10.1016/0024-3205(85)90381-9.CrossRef
23.
go back to reference Long WK, Carson PE: Increased erythrocyte glutathione reductase activity in diabetes mellitus. Biochem Biophys Res Commun. 1961, 5: 394-399. 10.1016/0006-291X(61)90047-X.CrossRef Long WK, Carson PE: Increased erythrocyte glutathione reductase activity in diabetes mellitus. Biochem Biophys Res Commun. 1961, 5: 394-399. 10.1016/0006-291X(61)90047-X.CrossRef
24.
go back to reference Lowry OH, Rosebrough NJ, Farr AL, Randall RG: Protein measurement with Folin reagent. J Biol Chem. 1951, 193: 265-275. Lowry OH, Rosebrough NJ, Farr AL, Randall RG: Protein measurement with Folin reagent. J Biol Chem. 1951, 193: 265-275.
25.
go back to reference Norusis MJ: SPSS professional statistics 6.1. 1994, SPSS Inc., Chicago, IL, 385- Norusis MJ: SPSS professional statistics 6.1. 1994, SPSS Inc., Chicago, IL, 385-
26.
go back to reference Martínez C: The epidemiology and etiology of hepatocarcinoma. Rev Esp Enferm Dig. 1994, 86: 665-671. Martínez C: The epidemiology and etiology of hepatocarcinoma. Rev Esp Enferm Dig. 1994, 86: 665-671.
27.
go back to reference Nakae D, Kobayashi Y, Akai H, Andoh N, Satoh H, Ohashi K, Tsutsumi M, Konishi Y: Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiet hylamine. Cancer Res. 1997, 57: 1281-1287. Nakae D, Kobayashi Y, Akai H, Andoh N, Satoh H, Ohashi K, Tsutsumi M, Konishi Y: Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiet hylamine. Cancer Res. 1997, 57: 1281-1287.
28.
go back to reference Ampy FR, Williams AO: Dimethylnitrosamine metabolism: I. In vitro activation of dimethylnitrosamine to mutagenic substance(s) by hepatic and renal tissues from three inbred strains of mice. Life Sci. 1986, 39: 923-930. 10.1016/0024-3205(86)90374-7.CrossRef Ampy FR, Williams AO: Dimethylnitrosamine metabolism: I. In vitro activation of dimethylnitrosamine to mutagenic substance(s) by hepatic and renal tissues from three inbred strains of mice. Life Sci. 1986, 39: 923-930. 10.1016/0024-3205(86)90374-7.CrossRef
29.
go back to reference Jeong JH, An JY, Kwon YT, Rhee JG, Lee YJ: Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J Cell Biochem. 2009, 106 (1): 73-82. 10.1002/jcb.21977.CrossRef Jeong JH, An JY, Kwon YT, Rhee JG, Lee YJ: Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. J Cell Biochem. 2009, 106 (1): 73-82. 10.1002/jcb.21977.CrossRef
30.
go back to reference Wang IK, Lin-Shiau SY, Lin JK: Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur J Cancer. 1999, 35: 1517-1525. 10.1016/S0959-8049(99)00168-9.CrossRef Wang IK, Lin-Shiau SY, Lin JK: Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur J Cancer. 1999, 35: 1517-1525. 10.1016/S0959-8049(99)00168-9.CrossRef
31.
go back to reference Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S: Quercetin Induces Apoptosis via Caspase Activation, Regulation of Bcl-2, and Inhibition of PI-3-Kinase/Akt and ERK Pathways in a Human Hepatoma Cell Line (HepG2). J Nutr. 2006, 136: 2715-2721. Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S: Quercetin Induces Apoptosis via Caspase Activation, Regulation of Bcl-2, and Inhibition of PI-3-Kinase/Akt and ERK Pathways in a Human Hepatoma Cell Line (HepG2). J Nutr. 2006, 136: 2715-2721.
32.
go back to reference Chaumontet C, Suschetet M, Honikman-Leban E, Krutovskikh VA, Berges R, Le Bon AM, Heberden C, Shahin MM, Yamasaki H, Martel P: Lack of tumor-promoting effects of flavonoids: Studies on rat liver preneoplastic foci and on in vivo and in vitro gap junctional intercellular communication. Nutr Cancer. 1996, 26: 251-263.CrossRef Chaumontet C, Suschetet M, Honikman-Leban E, Krutovskikh VA, Berges R, Le Bon AM, Heberden C, Shahin MM, Yamasaki H, Martel P: Lack of tumor-promoting effects of flavonoids: Studies on rat liver preneoplastic foci and on in vivo and in vitro gap junctional intercellular communication. Nutr Cancer. 1996, 26: 251-263.CrossRef
33.
go back to reference Avila MA, Juan AV, José C, Vicente N: Quercetin Mediates the Down-Regulation of Mutant p53 in the Human Breast Cancer Cell Line MDA-MB468. Cancer Research. 1994, 54: 2424-2428. Avila MA, Juan AV, José C, Vicente N: Quercetin Mediates the Down-Regulation of Mutant p53 in the Human Breast Cancer Cell Line MDA-MB468. Cancer Research. 1994, 54: 2424-2428.
34.
go back to reference Takehiro E, Tang Q, Denda A, Noguchi O, Kobayashi E, Tamura K, Horiguchi K, Ogasawara H, Tsujiuchi T, Nakae D, Sugimura1 M, KonLshi Y: Inhibition by acetylsalicylic acid, a cyclo-oxygenase inhibitor, and p-bromophenacylbromide, a phospholipase A2 inhibitor, of both cirrhosis and enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats. Carcinogenesis. 1996, 17: 467-475. 10.1093/carcin/17.3.467.CrossRef Takehiro E, Tang Q, Denda A, Noguchi O, Kobayashi E, Tamura K, Horiguchi K, Ogasawara H, Tsujiuchi T, Nakae D, Sugimura1 M, KonLshi Y: Inhibition by acetylsalicylic acid, a cyclo-oxygenase inhibitor, and p-bromophenacylbromide, a phospholipase A2 inhibitor, of both cirrhosis and enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats. Carcinogenesis. 1996, 17: 467-475. 10.1093/carcin/17.3.467.CrossRef
Metadata
Title
Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences
Authors
AlaaEddeen M Seufi
Safinz S Ibrahim
Tarek K Elmaghraby
Elsayed E Hafez
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2009
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-28-80

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