ANTI-TUMOUR TREATMENT Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma Anupam Bishayee * , Themos Politis, Altaf S. Darvesh Department of Pharmaceutical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA article info Article history: Received 7 July 2009 Received in revised form 8 October 2009 Accepted 9 October 2009 Keywords: Chemoprevention Chemotherapy Clinical study Hepatocarcinogenesis Hepatocellular carcinoma In vitro In vivo Liver Pharmacokinetics Resveratrol summary Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases in the world. Although the majority of HCC cases occur in developing countries of Asia and Africa, the prevalence of liver cancer has risen considerably in Japan, Western Europe as well as the United States. HCC most commonly develops in patients with chronic liver disease, the etiology of which includes viral hepatitis (B and C), alcohol, obesity, iron overload and dietary carcinogens, including aflatoxins and nitrosamines. The current treatment modalities, including surgical resection and liver transplantation, have been found to be mostly ineffective. Hence, there is an obvious critical need to develop alternative strategies for the chemopreven- tion and treatment of HCC. Oxidative stress as well as inflammation has been implicated in the develop- ment and progression of hepatic neoplasia. Using naturally occurring phytochemicals and dietary compounds endowed with potent antioxidant and antiinflammatory properties is a novel approach to pre- vent and control HCC. One such compound, resveratrol, present in grapes, berries, peanuts as well as red wine, has emerged as a promising molecule that inhibits carcinogenesis with a pleiotropic mode of action. This review examines the current knowledge on mechanism-based in vitro and in vivo studies on the chemopreventive and chemotherapeutic potential of resveratrol in liver cancer. Pre-clinical and clinical toxicity studies as well as pharmacokinetic data of resveratrol have also been highlighted in this review. Future directions and challenges involved in the use of resveratrol for the prevention and treatment of HCC are also discussed. Ó 2009 Elsevier Ltd. All rights reserved. Introduction Primary liver cancer, also known as hepatocellular carcinoma (HCC), happens to be the sixth most common cancer as well as the third leading cause of cancer mortality in the world. 1 HCC has a poor prognosis with the number of deaths almost equal to the number of cases being diagnosed annually (about 600,000) and the 5-year survival rate reported below 9%. 2 The incidence of HCC is on the rise in multiple geographic areas, including Asia Pa- cific, sub-Saharan Africa, southern Europe as well as North Amer- ica. The occurrence of HCC in the United States has dramatically increased by more than 70% over the last 25 years. 3 It has been estimated that there will be more than 22,000 new cases and about 18,000 deaths in the United States in 2009 due to liver cancer which represents about 4% of cancer mortality in this country. 4 The vast majority of HCC cases are attributable to underlying infec- tions caused by the hepatitis B and C viruses 5 ; nevertheless several other risk factors, namely alcoholism, obesity, iron overload, as well as dietary carcinogens, such as aflatoxins and nitrosamines are also involved in its etiology. 6–9 Although surgical resection is currently considered to be the most optimal treatment approach, only 10–20% of HCC patients are candidates for surgery because of tumor size, multifocality, vascular invasion, or hepatic decompensation. In addition, for those undergoing resection, the recurrence rates can be as high as 50% within several years of surgery. 10 While liver transplanta- tion has been successful for the treatment of early-stage liver can- cer, regrettably only a small number of HCC patients qualify for transplantation. The potential of this option is limited due to donor organ shortage as well as the rapid and frequent recurrence of HCC in the transplanted liver. At present, there is no proven effective systemic chemotherapy for HCC. Sorafenib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, has been shown to prolong the median survival time by nearly three months in pa- tients with advanced HCC. 11 Although sorafenib has been approved by the United States Food and Drug Administration for the treat- ment of unresectable HCC, recent studies indicate severe adverse effects including a significant risk of bleeding. 12 Alternative treat- ment modalities including transcatheter arterial chemoemboliza- tion, targeted intra-arterial delivery of Yttrium-90 microspheres, percutaneous intratumor ethanol injection, and radiofrequency ablation are primarily for palliation and are applicable only to pa- tients with localized liver tumors. In view of the limited treatment and grave prognosis of liver cancer, preventive control approaches, 0305-7372/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2009.10.002 * Corresponding author. Tel.: +1 330 325 6449; fax: +1 330 325 5936. E-mail address: abishayee@neoucom.edu (A. Bishayee). Cancer Treatment Reviews 36 (2010) 43–53 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv