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2015 | 62 | 3 | 573-580
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Current concepts in pathophysiology and management of hepatocellular carcinoma

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Additional approaches to control malignancies are needed due to the emerging trends in the incidence of cancer of different organ sites. Due to the high frequency of hepatocellular carcinoma (HCC) and its poor prognosis, preventing HCC is an urgent priority. To explore the antioxidant and apoptotic pathways of grape seed extract (GSE) we induce HCC experimentally by diethylnitrosoamine (DEN) and treated the animals with low and high doses of GSE. The results indicate good therapeutic possibilities for GSE use in treatment of HCC., This was evidenced via regression of liver enzymes' function (ALT&AST), the HCC markers; α-fucosidase, α-fetoprotein and carcinoembrionic antigen (CEA) in HCC groups treated with the grape seed extract. Also, tumor necrosis factor (TNF-α) showed a significant decrease using GSE in HCC bearing animals. Regarding the apoptotic pathways of GSE, we found a significant down regulation of apoptosis enhancing nuclease (Aen), Bcl2-associated X protein (Bax), B-cell translocation gene 2(Btg2), Cyclin G1 (Ccng1) and Cyclin-dependent kinase inhibitor 1A (Cdkn1a) gene expression in HCC+GSE groups as compared to HCC bearing group. In the same trend, the necrotic/apoptotic rates were significantly higher in the HCC groups treated with GSE vs. the HCC bearing group. Finally, the 8-OHdG/2-dG generation decreased by 73.8% and 52.9% in HCC+GSE at low and high doses, respectively. Based on these encouraging observations, grape seed extract could be a promising natural remedy for attenuating hepatocellular carcinoma that has a great future in approaches directed towards control of HCC.
Physical description
  • Biochemistry Department, Faculty of Science for Girls, King Abdulaziz University, Jeddah, KSA
  • Biochemistry and Nutrition Department, Faculty of Women, Ain Shams University, Cairo, Egypt
  • Biochemistry and Nutrition Department, Faculty of Women, Ain Shams University, Cairo, Egypt
  • Biochemistry Department, Faculty of Science for Girls, King Abdulaziz University, Jeddah, KSA
  • Biochemistry and Nutrition Department, Faculty of Women, Ain Shams University, Cairo, Egypt
  • National Research Centre, Cell Biology Department, Dokki, Giza, Egypt
  • National Research Centre, Hormones Department, Dokki, Giza, Egypt
  • A.O.A.C. (1995) Official methods of analysis. 16th ed. Association of official analysis, Wahington DC.
  • Baig JA, Alam JM, Mahmood SR, Baig M, Shaheen R, Sultana I, Waheed A (2009) Hepatocellular Carcinoma (HCC) and Diagnostic Significance of alpha-Fetoprotein (AFP). J Ayub Med Coll Abbottabad 21: 72-75.
  • Baliga MS, Katiyar SK (2006) Chemoprevention of photocarcinogenesis by selected dietary botanicals. Photochem Photobiol Sci 5: 243-253.
  • Barnes JM, Paget GE (1965) Mechanisms of toxic action. Prog Med Chem 4: 18-38.
  • Bianchini F, Vainio H (2003) Wine and resveratrol: mechanisms of cancer prevention? Eur J Cancer Prev 12: 417-425.
  • Cao J, Jiang L, Zhang X, Yao X, Geng C, Xue X, Zhong L. (2008) Boric acid inhibits LPS-induced TNF-alpha formation through a thiol-dependent mechanism in THP-1 cells. J Trace Elem Med Biol 22: 189-195.
  • Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP (2005) Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol 69: 1421-1432.
  • Corti A, Fassina G, Marcucci F, Barbanti E, Cassani G (1992) Oligomeric tumour necrosis factor alpha slowly converts into the reactive forms at bioactive levels. Biochem J 284: 905-910.
  • Czene S, Testa E, Nygren J, Belyaev I, Harms-Ringdahl M (2002) DNA fragmentation and morphological changes in apoptotic human lymphocytes. Biochem Biophys Res Commun 294: 872-878.
  • Dhanalakshmi S, Agarwal R, Agarwal C (2003) Inhibition of NF-kappaB pathway in grape seed extract-induced apoptotic death of human prostate carcinoma DU145 cells. Int J Oncol 23: 721-727.
  • El Mesallamy HO, Metwally NS, Soliman MS, Ahmed KA, Abdel Moaty MM (2011) The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats. Cancer Cell Int 11: 38.
  • El-Beshbishy HA, Mohamadin AM, Nagy AA, Abdel-Naim AB (2010) Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin. Indian J Exp Biol 48: 280-288.
  • El-Serag HB (2002) Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol 35 (Suppl 2): S72-S78.
  • Girgis E, Khalil WK, Emam AN, Mohamed MB, Rao KV (2012) Nanotoxicity of gold and gold-cobalt nanoalloy. Chem Res Toxicol 25: 1086-1098.
  • Heintges T, Wands JR (1997) Hepatitis C virus: epidemiology and transmission. Hepatology 26: 521-526.
  • Hoorens A, Pipeleers D (1999) Nicotinamide protects human beta cells against chemicallyinduced necrosis, but not against cytokine-induced apoptosis. Diabetologia 42: 55-59.
  • Jo JY, Gonzalez de Mejia E, Lila MA (2005) Effects of grape cell culture extracts on human topoisomerase II catalytic activity and characterization of active fractions. J Agric Food Chem 53: 2489-2498.
  • Karimov KY, Inoyatova FK, Mukhamedova MT (2003) Changes in some indices of the synthesis of nitric oxide during the early stages of hepatocarcinogenesis. Exp Toxicol Pathol 55: 17-19.
  • Khalil WK, Booles HF (2011) Protective role of selenium against over-expression of cancer-related apoptotic genes induced by o-cresol in rats. Arh Hig Rada Toksikol 62: 121-129.
  • Khalil WK, Girgis E, Emam AN, Mohamed MB, Rao KV (2011) Genotoxicity evaluation of nanomaterials: DNA damage, micronuclei, and 8-hydroxy-2-deoxyguanosine induced by magnetic doped CdSe quantum dots in male mice. Chem Res Toxicol 24: 640-650.
  • Khoshbaten M, Aliasgarzadeh A, Masnadi K, Farhang S, Tarzamani MK, Babaei H, Kiani J, Zaare M, Najafipoor F (2010) Grape seed extract to improve liver function in patients with nonalcoholic fatty liver change. Saudi J Gastroenterol 16: 194-197.
  • Kweon S, Kim Y, Choi H (2003) Grape extracts suppress the formation of preneoplastic foci and activity of fatty acid synthase in rat liver. Exp Mol Med 35: 371-378.
  • Li J, Li J, Li S, He B, Mi Y, Cao H, Zhang C, Li L (2012) Ameliorative effect of grape seed proanthocyanidin extract on thioacetamide-induced mouse hepatic fibrosis. Toxicol Lett 213: 353-360.
  • Liu YF, Zha BS, Zhang HL, Zhu XJ, Li YH, Zhu J, Guan XH, Feng ZQ, Zhang JP (2009) Characteristic gene expression profiles in the progression from liver cirrhosis to carcinoma induced by diethylnitrosamine in a rat model. J Exp Clin Cancer Res 28: 107.
  • Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105: 2862-2868.
  • Miura D, Miura Y, Yagasaki K (2003) Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatomabearing rats. Life Sci 73: 1393-1400.
  • Othman AM, El-Houseini ME, El-Sofy MS, Aboul-Enein HY (2011) Potentiometric determination of α-l-fucosidase enzyme by using 2-chloro-4-nitrophenol-rhodamine B ion pair chemical recognition in PVC membrane sensor. Anal Bioanal Chem 400: 787-795.
  • Pan X, Dai Y, Li X, Niu N, Li W, Liu F, Zhao Y, Yu Z (2011) Inhibition of arsenic-induced rat liver injury by grape seed exact through suppression of NADPH oxidase and TGF-β/Smad activation. Toxicol App Pharmacol 254: 323-331.
  • Pradeep K, Mohan CV, Gobianand K, Karthikeyan S (2007) Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol 560: 110-116.
  • Puiggros F, Llopiz N, Ardevol A, Blade C, Arola L, Salvado MJ (2005) Grape seed procyanidins prevent oxidative injury by modulating the expression of antioxidative enzyme systems. J Agric Food Chem 53: 6080-6086.
  • Reitman S, Frankel S (1957) Colorimetric method for AST or ALT activity. Am J Clin Pathol 28: 57-63.
  • Schwartz MK (1987) Tumor markers in diagnosis and screening. In Human Tumor markers. pp 3-16.
  • Senthilkumar S, Ebenezar KK, Sathish V, Yogeeta S, Devaki T (2006) Modulation of the tissue defense system by squalene in cyclophosphamide induced toxicity in rats. Arch Med Sci 2: 94-100.
  • Singh RP, Tyagi AK, Dhanalakshmi S, Agarwal R, Agarwal C (2004) Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. Int J Cancer 108: 733-740.
  • Sivaramakrishnan V, Shilpa PN, Praveen Kumar D, Niranjali Devaraj S (2007) Attenuation of N-nitrosodiethylamine-induced hepatocellular carcinogenesis by a novel flavonol-Morin. Chem Biol Interact 171: 79-78.
  • Suenaga K, Takasawa H, Watanabe T, Wako Y, Suzuki T, Hamada S, Furihata C (2013) Differential gene expression profiling between genotoxic and non-genotoxic hepatocarcinogens in young rat liver determined by quantitative real-time PCR and principal component analysis. Mutat Res 751: 73-83.
  • Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, Lauwers GY, Kulu Y, Muzikansky A, Kuruppu D, Lanuti M, Goodwin JM, Azoulay D, Fuchs BC (2008) Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 299: 53-60.
  • Tang Q, Zou P, Jin H, Fu J, Yang J, Shang L, Wei X (2012) Grape-seed proanthocyanidins ameliorate contact hypersensitivity induced by 2,4-dinitrofluorobenzene (DNFB) and inhibit T cell proliferation in vitro. Toxicol Lett 210: 1-8.
  • Verna L, Whysner J, Williams GM (1996) N-Nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther 71: 57-81.
  • Watanabe T, Suzuki T, Natsume M, Nakajima M, Narumi K, Hamada S, Sakuma T, Koeda A, Oshida K, Miyamoto Y, Maeda M et al. (2012) Discrimination of genotoxic and non-genotoxic hepatocarcinogens by statistical analysis based on gene expression profiles in mouse liver as determined by quantitative real-time PCR. Mutat Res 747: 164-173.
  • Watanabe T, Tanaka G, Hamada S, Namiki C, Suzuki T, Nakajima M, Furihata C (2009) Dose-dependent alterations in gene expression in mouse liver induced by diethylnitrosamine and ethylnitrosourea and determined by quantitative real-time PCR. Mutat Res 673: 9-20.
  • Weber LW, Boll M, Stampfl A (2003) Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 33: 105.
  • Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, Fiel I, Thung S, Mazzaferro V, Bruix J, Bottinger E, Friedman S, Waxman S, Llovet JM (2007) Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45: 938-947.
  • Yao DF, Dong ZZ, Yao M (2007) Specific molecular markers in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 6: 241-247.
  • Ye X, Krohn RL, Liu W, Joshi SS, Kuszynski CA, McGinn TR, Bagchi M, Preuss HG, Stohs SJ, Bagchi D (1999) The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol Cell Biochem 196: 99-108.
  • Zhao J, Wang J, Chen Y, Agarwal R (1999) Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seed in the mouse skin two-stage initiation-promotion protocol and identification of procyanidin B5-30-gallate as the most effective antioxidant constituent. Carcinogenesis 20: 1737-1745.
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