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Suppression of the Inflammatory Cascade is Implicated in Resveratrol Chemoprevention of Experimental Hepatocarcinogenesis

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ABSTRACT

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-κB (NF-κB), 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-κB p65 from the cytosol to the nucleus with stabilization of inhibitory κB.

Conclusion

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-κB. 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.

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Abbreviations

COX-2:

cyclooxygenase-2

DENA:

diethylnitrosamine

HBV:

hepatitis B virus

HCC:

hepatocellular carcinoma

HCV:

hepatitis C virus

HRP:

horseradish peroxidase

HSP70:

heat shock protein 70

IκB:

inhibitor of κB

iNOS:

inducible nitric oxide synthase

NF-κB:

nuclear factor-kappa B

PB:

phenobarbital

PBS:

phosphate-buffered saline

PGs:

prostaglandins

ROS:

reactive oxygen species

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ACKNOWLEDGMENTS

This work was supported by a Research Incentive Grant from Ohio Board of Regents, State of Ohio. The authors sincerely thank Cornelis Van der Schyf, D.Sc., DTE, for his constant support and encouragement, Howard P. Glauert, Ph.D., for helpful discussions, and Werner J. Geldenhuys, Ph.D., for technical assistance with the structure of resveratrol.

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Authors and Affiliations

  1. 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

    Anupam Bishayee, Abhijeet Waghray, Kendra F. Barnes, Thomas Mbimba, Deepak Bhatia & Altaf S. Darvesh

  2. Department of Pharmaceutical Technology, Division of Biochemistry, Jadavpur University, Kolkata, 700 032, India

    Malay Chatterjee

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  1. Anupam Bishayee
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Correspondence to Anupam Bishayee.

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Bishayee, A., Waghray, A., Barnes, K.F. et al. Suppression of the Inflammatory Cascade is Implicated in Resveratrol Chemoprevention of Experimental Hepatocarcinogenesis. Pharm Res 27, 1080–1091 (2010). https://doi.org/10.1007/s11095-010-0144-4

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