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Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma

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Summary

Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action. Recently, we have reported that dietary resveratrol significantly prevents chemically-induced liver tumorigenesis in rats. One of the mechanisms of resveratrol-mediated chemoprevention of hepatocarcinogenesis could be related to its antiinflammatory action through hepatic cyclooxygenase (COX-2) inhibition. Although several COX-2 inhibitors are known to exert chemopreventive efficacy, not all are considered ideal candidates for chemoprevention due to the risk of adverse cardiovascular events. Accordingly, the objective of the present study was to evaluate the role of resveratrol on cardiac performance during experimental hepatocarcinogenesis initiated with diethylnitrosamine and promoted by phenobarbital. Rats had free access to diet supplemented with resveratrol four weeks before the carcinogen injection and 14 weeks thereafter. The cardiotoxicity of resveratrol was assessed by monitoring the cardiac function using transthoracic echocardiography as well as Western blot analysis of cardiac tissue. Long-term dietary administration of resveratrol dose-dependently suppressed hepatic tumor multiplicity, the principal endpoint for evaluating the chemopreventive potential of a candidate agent. The chemopreventive effects of resveratrol were also reflected in histopathological assessment of hepatic tissues. Resveratrol did not exhibit any cardiotoxicity but rather improved the cardiac function in a dose-responsive fashion. Our results indicate that resveratrol-mediated chemoprevention of rat liver carcinogenesis is devoid of any adverse cardiovascular events. Resveratrol may be developed as a chemopreventive as well as therapeutic drug for human HCC.

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Acknowledgments

The authors like to thank William M. Chilian, Ph.D., for providing infrastructural facilities and helpful suggestions for echocardiograpy study, Cornelis Van der Schyf, D.Sc., DTE, for constant encouragement, and Cindy L. Fobes for providing the care and maintenance of the animals. We also thank Altaf S. Darvesh, M.Pharm., Ph.D., for reviewing the manuscript and providing excellent feedback and comments. This work was supported in part by a Research Incentive grant from Ohio Board of Regents, State of Ohio.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH, 44272, USA

    Daniel J. Luther, Vahagn Ohanyan, Patricia E. Shamhart, Cheryl M. Hodnichak & J. Gary Meszaros

  2. Graduate Program, School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA

    Daniel J. Luther, Patricia E. Shamhart, J. Gary Meszaros & Anupam Bishayee

  3. Department of Internal Diseases 1, Cardiology Division, University Hospital 1, Yerevan State Medical University, Yerevan, Armenia

    Hamayak Sisakian

  4. Innovative Drug Development, Pharmascience Inc., 6111 Royalmount Avenue, Montréal, Québec, H4P 2T4, Canada

    Tristan D. Booth

  5. Department of Pharmaceutical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH, 44272, USA

    Anupam Bishayee

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  1. Daniel J. Luther
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Correspondence to Anupam Bishayee.

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Daniel J. Luther and Vahagn Ohanyan contributed equally to this work.

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Luther, D.J., Ohanyan, V., Shamhart, P.E. et al. Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma. Invest New Drugs 29, 380–391 (2011). https://doi.org/10.1007/s10637-009-9332-7

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