Alteration of hepatic proinflammatory cytokines is involved in the resveratrol-mediated chemoprevention of chemically-induced hepatocarcinogenesis.
Female; Animals; Rats; Gene Expression Regulation/drug effects; Liver/drug effects/metabolism; Resveratrol; Diethylnitrosamine; Anticarcinogenic Agents/pharmacology/*therapeutic use; Cytokines/genetics/*metabolism; Phenobarbital; Stilbenes/pharmacology/*therapeutic use; Sprague-Dawley; RNA; Messenger/metabolism; Liver Neoplasms; Experimental/chemically induced/metabolism/*prevention & control
Hepatocellular carcinoma (HCC), one of the most common cancers in the world, is a leading cause of cancerrelated mortality. HCC develops most frequently in the background of oxidative stress and chronic hepatic inflammation due to viral infections, alcohol abuse as well as exposure to environmental and dietary carcinogens. As the prognosis of HCC is extremely poor and mostly unresponsive to current chemotherapeutic treatment regimens, novel preventive approaches like chemoprevention are urgently needed. We have recently found that resveratrol, a dietary polyphenol present in grapes, berries, peanuts as well as red wine, prevents diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats through suppression of inflammation and oxidative stress. As cytokines are considered to be important mediators of inflammation, the objective of the present study was to investigate the effects of resveratrol on hepatic cytokines during DENA-initiated hepatocarcinogenesis in rats. Liver samples were harvested from our previous study in which resveratrol (50, 100 and 300 mg/kg) was found to exert a chemopreventive action against rat liver tumorigenesis induced by DENA. The levels of proinflammatory cytokines, namely tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin- 6 (IL-6), were measured using enzyme-linked immunosorbent assays. The mRNA expression of these cytokines was studied by reverse transcriptase-polymerase chain reaction for comparison. Resveratrol treatment reversed the DENAinduced alteration of the level and expression of hepatic TNF-alpha, IL-1beta and IL-6. From the current results in conjunction with our previous findings, it can be concluded that resveratrol-mediated chemoprevention of rat liver carcinogenesis is related to alteration of proinflammatory cytokines.
Mbimba Thomas; Awale Prabha; Bhatia Deepak; Geldenhuys Werner J; Darvesh Altaf S; Carroll Richard T; Bishayee Anupam
Current pharmaceutical biotechnology
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/138920112798868575" target="_blank" rel="noreferrer noopener">10.2174/138920112798868575</a>
Anthocyanin-rich black currant (Ribes nigrum L.) extract affords chemoprevention against diethylnitrosamine-induced hepatocellular carcinogenesis in rats.
Animals; Anthocyanins/*therapeutic use; Anticarcinogenic Agents/therapeutic use; Apoptosis/drug effects; bcl-2-Associated X Protein/metabolism; Cell Proliferation/drug effects; Chemoprevention; Diethylnitrosamine; Down-Regulation; Experimental/metabolism/pathology; Liver Neoplasms; Liver Neoplasms/chemically induced/*prevention & control; Liver/pathology; Male; Phenobarbital; Plant Extracts/*therapeutic use; Proliferating Cell Nuclear Antigen/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; Rats; Ribes/chemistry; Sprague-Dawley; Up-Regulation
Anthocyanins are known to possess potent anticarcinogenic properties against several cancers thus demonstrating potential for cancer prevention. Black currant (Ribes nigrum L., Grossulariaceae) fruits have a high anthocyanin content. This "superfruit" is known to possess various pharmacological effects including alleviation of chronic oxidative stress and inflammation. In contrast to a large volume of literature on the health benefits of black currant, limited evidence on antitumor effects of black currant exists with virtually no data on the prevention of experimental carcinogenesis. In the current study, we have investigated the chemopreventive effects of an anthocyanin-rich black currant skin extract (BCSE) utilizing our well-characterized model of rat liver carcinogenesis. Initiation of hepatocarcinogenesis was done by intraperitoneal injection of diethylnitrosamine (DENA) followed by promotion with phenobarbital. The rats were exposed to dietary BCSE for 4 weeks prior to initiation, and the treatment was continued for 22 consecutive weeks. BCSE dose-dependently decreased the incidence, total number, multiplicity, size and volume of preneoplastic hepatic nodules. The antihepatocarcinogenic effect of BCSE was confirmed by histopathological examination of liver sections. Immunohistochemical analysis of proliferating cell nuclear antigen and DNA fragmentation revealed BCSE-mediated inhibition of abnormal cell proliferation and induction of apoptosis in
Bishayee Anupam; Mbimba Thomas; Thoppil Roslin J; Haznagy-Radnai Erzsebet; Sipos Peter; Darvesh Altaf S; Folkesson Hans G; Hohmann Judit
The Journal of nutritional biochemistry
2011
2011-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.jnutbio.2010.09.001" target="_blank" rel="noreferrer noopener">10.1016/j.jnutbio.2010.09.001</a>
Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis.
Animal; Animals; Anticarcinogenic Agents/*antagonists & inhibitors/pharmacology; Antitumor; Apoptosis/*drug effects; Body Weight/drug effects; Cell Proliferation/drug effects; Diethylnitrosamine; Disease Models; Dose-Response Relationship; Drinking/drug effects; Drug; Drug Screening Assays; Eating/drug effects; Experimental/chemically induced/pathology/*prevention & control; Female; Immunohistochemistry; Liver Neoplasms; Organ Size/drug effects; Phenobarbital; Proto-Oncogene Proteins c-bcl-2/biosynthesis; Rats; Resveratrol; Sprague-Dawley; Stilbenes/*pharmacology
Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases. In view of the limited treatment and a grave prognosis of liver cancer, preventive control has been emphasized. Resveratrol, a polyphenol found in grape skins, peanuts, berries and red wine, has been shown to possess potent growth inhibitory effects against various human cancer cells. Although resveratrol has been found to exhibit chemopreventive actions in experimentally induced skin, breast, colon and esophagus rodent tumors, chemopreventive potential of this dietary constituent has not been explored well against experimental liver cancer. We evaluated the inhibitory effect of resveratrol using a two-stage model of rat hepatocarcinogenesis in Sprague-Dawley rats. Initiation was performed by a single intraperitoneal injection of diethylnitrosamine (DENA, 200 mg/kg), followed by promotion with phenobarbital (0.05%) in drinking water. The rats had free access to food supplemented with resveratrol equivalent to 50, 100 or 300 mg/kg body weight/day. Resveratrol treatment was started 4 weeks prior to the initiation and continued for 20 weeks. Resveratrol dose-dependently reduced the incidence, total number and multiplicity of visible hepatocyte nodules. Mean nodular volume and nodular volume as percentage of liver volume were also inhibited upon resveratrol treatment. Histopathological examination of liver tissue confirmed the protective effect of resveratrol. Immunohistochemical detection of cell proliferation and assay of apoptosis indicated a decrease in cell proliferation and increase of apoptotic cells in the livers of resveratrol-supplemented rats. Resveratrol also induced the expression of pro-apoptotic protein Bax, reduced anti-apoptotic Bcl-2 expression, with a concurrent increase in Bax/Bcl-2 ratio with respect to DENA control. The present study provides evidence, for the first time, that resveratrol exerts a significant chemopreventive effect on DENA-initiated hepatocarcinogenesis through inhibition of cell proliferation and induction of apoptosis. Resveratrol-induced apoptogenic signal during rat liver carcinogenesis may be mediated through the downregulation of Bcl-2 and upregulation of Bax expression. Due to a favorable toxicity profile, resveratrol can potentially be developed as a chemopreventive drug against human HCC.
Bishayee Anupam; Dhir Neetika
Chemico-biological interactions
2009
2009-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.cbi.2008.11.015" target="_blank" rel="noreferrer noopener">10.1016/j.cbi.2008.11.015</a>
Suppression of the inflammatory cascade is implicated in resveratrol chemoprevention of experimental hepatocarcinogenesis.
Animals; Anticarcinogenic Agents/*therapeutic use; Chemoprevention; Cyclooxygenase 2/immunology; Diethylnitrosamine; Female; HSP70 Heat-Shock Proteins/immunology; Humans; Inflammation/prevention & control; Liver Neoplasms/chemically induced/*immunology/*prevention & control; Liver/drug effects/pathology; NF-kappa B/immunology; Rats; Resveratrol; Sprague-Dawley; Stilbenes/*therapeutic use
PURPOSE: 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
Bishayee Anupam; Waghray Abhijeet; Barnes Kendra F; Mbimba Thomas; Bhatia Deepak; Chatterjee Malay; Darvesh Altaf S
Pharmaceutical research
2010
2010-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s11095-010-0144-4" target="_blank" rel="noreferrer noopener">10.1007/s11095-010-0144-4</a>
Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis.
Acute/chemically induced; Animals; Carcinoma; Cell Movement; Cell Proliferation/drug effects; Diethylnitrosamine; G-Protein-Coupled/*deficiency; Hepatocellular/*chemically induced; Humans; Liver Failure; Liver Neoplasms/*chemically induced; Mice; Phosphorylation; Receptors; STAT3 Transcription Factor/physiology; Tumor Suppressor Proteins/*physiology
UNLABELLED: Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. TGR5 activation also inhibits nuclear factor kappaB (NF-kappaB)-mediated inflammation. Here we show that TGR5 deficiency enhances chemically induced liver carcinogenesis, and that TGR5 is a negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling. Mice lacking TGR5 were much more susceptible to diethylnitrosamine (DEN)-induced acute liver injury and liver carcinogenesis than wildtype (WT) mice. Consistent with the increasing incidence of liver cancer in TGR5(-/-) mice, hepatocyte death, compensatory proliferation, and gene expression of certain inflammatory cytokines and matrix metalloproteinases were more sensitive to DEN induction in the absence of TGR5 signaling. In vitro, TGR5 activation greatly inhibited proliferation and migration of human liver cancer cells. We then found that TGR5 activation strongly suppressed STAT3 signaling in vitro and in vivo. Furthermore, we observed that TGR5 antagonizes the STAT3 pathway through suppressing STAT3 phosphorylation, its transcription activity, and DNA binding activity, which suggests that TGR5 antagonizes liver tumorigenesis at least in part by inhibiting STAT3 signaling. CONCLUSION: These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer.
Chen Wei-Dong; Yu Donna; Forman Barry M; Huang Wendong; Wang Yan-Dong
Hepatology (Baltimore, Md.)
2013
2013-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.26019" target="_blank" rel="noreferrer noopener">10.1002/hep.26019</a>