Suppression of the inflammatory cascade is implicated in resveratrol chemoprevention of experimental hepatocarcinogenesis.
OBJECTIVE
Resveratrol, present in grapes and red wine, has been found to prevent diethylnitrosamine (DENA)-initiated rat liver tumorigenesis, though the chemopreventive mechanisms are not completely elucidated. The current study was designed to explore whether the antiinflammatory properties of resveratrol play a role in its antihepatocarcinogenic action.


METHODS
Liver samples were harvested from a 20-week chemopreventive study in which resveratrol (50, 100 and 300 mg/kg) was shown to inhibit DENA-induced hepatocyte nodules in Sprague-Dawley rats in a dose-responsive manner. Hepatic preneoplastic and inflammatory markers, namely heat shock protein (HSP70), cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB), were studied using immunohistochemical as well as Western blot techniques.


RESULTS
Resveratrol dose-dependently suppressed DENA-induced increased expressions of hepatic HSP70 and COX-2. Resveratrol also attenuated the DENA-mediated translocation of NF-kappaB p65 from the cytosol to the nucleus with stabilization of inhibitory kappaB.


CONCLUSIONS
The present findings indicate that resveratrol exerts chemoprevention of hepatocarcinogenesis possibly through antiinflammatory effects during DENA-evoked rat liver carcinogenesis by suppressing elevated levels of HSP70, COX-2 as well as NF-kappaB. These beneficial effects combined with an excellent safety profile encourage the development of resveratrol for chemoprevention and intervention of human HCC that remains a devastating disease.
Bishayee
Anupam
A
Department of Pharmaceutical Sciences Cancer Therapeutics and Chemoprevention Emphasis Group, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown Ohio, 44272, USA. abishayee@neoucom.edu
Waghray
Abhijeet
A
Barnes
Kendra F
KF
Mbimba
Thomas
T
Bhatia
Deepak
D
Chatterjee
Malay
M
Darvesh
Altaf S
AS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D018890:Chemoprevention; D051546:Cyclooxygenase 2 / Q000276:immunology; D004052:Diethylnitrosamine; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D016328:NF-kappa B / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*
D016588:Anticarcinogenic Agents; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D013267:Stilbenes; D004052:Diethylnitrosamine; D051546:Cyclooxygenase 2; D000077185:Resveratrol
Cancer Lett. 2008 Oct 8;269(2):243-61
18550275
J Lab Clin Med. 2002 Apr;139(4):234-43
12024111
Dig Dis. 2009;27(2):80-92
19546545
Cell Res. 2008 Mar;18(3):334-42
18301380
Exp Clin Cardiol. 2006 Fall;11(3):217-25
18651034
Ann N Y Acad Sci. 2009 Feb;1155:206-21
19250206
Gastroenterology. 2004 Nov;127(5 Suppl 1):S27-34
15508094
Lancet. 2003 Dec 6;362(9399):1907-17
14667750
Cancer Prev Res (Phila). 2009 May;2(5):409-18
19401532
Hepatology. 1999 Mar;29(3):688-96
10051469
Mol Carcinog. 1989;2(5):233-6
2690852
Cell. 1995 Nov 3;83(3):493-501
8521479
Clin Cancer Res. 2009 Jan 15;15(2):425-30
19147746
Mol Nutr Food Res. 2009 Jan;53(1):115-28
19072742
Clin Cancer Res. 2001 May;7(5):1325-32
11350902
Pharmacol Res. 2009 May;59(5):330-7
19416633
Nature. 2003 Sep 11;425(6954):191-6
12939617
World J Gastroenterol. 2006 Aug 28;12(32):5113-21
16937518
Mol Carcinog. 2008 Oct;47(10):797-805
18381589
Asian Pac J Cancer Prev. 2008 Apr-Jun;9(2):295-8
18712978
Inflamm Allergy Drug Targets. 2007 Sep;6(3):168-73
17897053
Cancer Res. 1986 Oct;46(10):5106-11
3756868
Clin Cancer Res. 2005 Aug 1;11(15):5645-50
16061884
Anticancer Res. 2009 Feb;29(2):539-44
19331200
Mol Cancer Ther. 2008 Dec;7(12):3751-60
19074850
Cancer Prev Res (Phila). 2010 Jun;3(6):753-63
20501860
Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8
1380156
Nucleic Acids Res. 1983 Mar 11;11(5):1475-89
6828386
Cancer Prev Res (Phila). 2009 Mar;2(3):200-8
19258539
J Natl Cancer Inst. 2000 Oct 4;92(19):1564-72
11018092
J Biol Chem. 1994 Feb 18;269(7):4705-8
7508926
Chem Biol Interact. 2009 May 15;179(2-3):131-44
19073162
Eur J Cancer Prev. 2009 Feb;18(1):13-25
19077560
Ann N Y Acad Sci. 2009 Feb;1155:293-9
19250220
Biochem Pharmacol. 2006 May 14;71(10):1397-421
16563357
Cancer Lett. 2008 Oct 8;269(2):315-25
18467024
J Cancer Res Clin Oncol. 2009 Aug;135(8):969-81
19399516
Hepatology. 2007 Aug;46(2):590-7
17661407
Anticancer Res. 2003 Nov-Dec;23(6C):4921-6
14981946
Lab Invest. 1987 Jan;56(1):4-22
3025514
Biochem Biophys Res Commun. 1994 Aug 30;203(1):190-9
8074655
Mol Cells. 2004 Feb 29;17(1):35-8
15055524
Crit Rev Clin Lab Sci. 2000 Oct;37(5):431-502
11078056
Arch Biochem Biophys. 2009 Jun 15;486(2):95-102
19514131
J Korean Med Sci. 2005 Oct;20(5):829-34
16224158
Nat Immunol. 2002 Mar;3(3):221-7
11875461
Cancer Res. 2007 Oct 15;67(20):9844-51
17942915
Acta Pharmacol Sin. 2007 Sep;28(9):1331-42
17723167
J Nutr Sci Vitaminol (Tokyo). 2004 Feb;50(1):61-5
15228220
Semin Liver Dis. 2005;25(2):143-54
15918143
Cancer Sci. 2008 Jun;99(6):1109-16
18429957
Science. 1993 Mar 5;259(5100):1409-10
8451637
Gastroenterology. 2004 Nov;127(5 Suppl 1):S310-8
15508099
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
J Appl Toxicol. 2009 Mar;29(2):91-100
18937212
Mol Nutr Food Res. 2008 Jun;52 Suppl 1:S62-70
18551458
Biochem Pharmacol. 2006 Nov 30;72(11):1439-52
16920072
Cancer Res. 2000 Jul 1;60(13):3477-83
10910059
Curr Med Chem. 2008;15(11):1044-71
18473802
Cancer. 2003 Aug 15;98(4):661-7
12910508
Carcinogenesis. 1984 Nov;5(11):1381-93
6386215
J Appl Toxicol. 2008 Jan;28(1):35-43
17429801
Cancer Treat Rev. 2010 Feb;36(1):43-53
19910122
Anticancer Res. 2004 Sep-Oct;24(5A):2783-840
15517885
Carcinogenesis. 2008 Aug;29(8):1639-47
18579559
Mol Cell Biochem. 2008 Jun;313(1-2):53-61
18373278
Hepatology. 2003 Jan;37(1):198-207
12500205
Nutrition. 2009 Nov-Dec;25(11-12):1169-76
19818280
World J Gastroenterol. 2005 Apr 14;11(14):2072-9
15810071
Biochim Biophys Acta. 2000 Mar 27;1470(2):M69-78
10722929
Cancer Treat Rev. 2006 Feb;32(1):28-44
16337744
Lancet Oncol. 2009 Oct;10(10):967-74
19767240
Chem Biol Interact. 2009 Aug 14;180(3):353-9
19539802
J Gastroenterol Hepatol. 2001 Dec;16(12):1329-35
11851828