Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma

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 chemoprevention and treatment of HCC. Oxidative stress as well as inflammation has been implicated in the development and progression of hepatic neoplasia. Using naturally occurring phytochemicals and dietary compounds endowed with potent antioxidant and antiinflammatory properties is a novel approach to prevent 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.

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 Pacific, sub-Saharan Africa, southern Europe as well as North America. 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 infections caused by the hepatitis B and C viruses⁵; 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, 7, 8, 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 transplantation has been successful for the treatment of early-stage liver cancer, 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 patients with advanced HCC.¹¹ Although sorafenib has been approved by the United States Food and Drug Administration for the treatment of unresectable HCC, recent studies indicate severe adverse effects including a significant risk of bleeding.¹² Alternative treatment modalities including transcatheter arterial chemoembolization, targeted intra-arterial delivery of Yttrium-90 microspheres, percutaneous intratumor ethanol injection, and radiofrequency ablation are primarily for palliation and are applicable only to patients with localized liver tumors. In view of the limited treatment and grave prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered as one of the best strategies in lowering the current morbidity and mortality associated with HCC.13, 14 A detailed understanding of the pathogenesis of HCC holds the promise of finding an effective and novel strategy for the chemoprevention and treatment of liver cancer.

Although the cellular mechanisms contributing to hepatocarcinogenesis are relatively unknown, a connection between inflammation and liver cancer is beginning to be unraveled. During recent years, compelling evidence has accumulated which provides an insight in the role of inflammation in initiation, promotion and progression of HCC.¹⁵ Hepatic inflammation, due to exposure to infectious agents (hepatotropic viruses) as well as toxic compounds, may represent an early step in the development of malignancy with genetic and epigenetic events occurring as a later manifestation of a prolonged inflammatory process. Despite intrinsic differences among etiological factors for HCC, a common denominator of the genesis of malignancy happens to be the perpetuation of a wound-healing response triggered by parenchymal cell death, and the ensuing inflammatory reaction.16, 17 It has been shown that HCC almost always develops on a background of chronic liver injury including chronic hepatitis and cirrhosis, which are both considered to be preneoplastic stages of hepatocellular tumor development.¹⁸ An expanding body of evidence suggests that inflammation-mediated processes, including the production of cytokines, chemokines, reactive oxygen and nitrogen species, and mediators of the inflammatory pathways may contribute to hepatic neoplasia.19, 20, 21, 22 Environmental insults, including chemical toxicants, act as tumor initiators and/or promoters by inducing steady-state increase in the generation of reactive oxygen species (ROS).²³ Oxidative stress, through generation of ROS including singlet oxygen, superoxide anion, hydrogen peroxide and hydroxyl radical, acts as a predisposing factor to hepatocarcinogenesis and is the common driving force of HCC in chronic liver diseases.19, 24 All these findings have led researchers to theorize that the underlying mechanisms which are most pronounced in occurrence and progression of HCC deal with oxidative stress and the accompanying inflammatory insults.

Phytochemicals are widely accepted as validated treatment options for various conditions. Scientific probing into potential benefits of many of these compounds sufficiently defines them as beneficial pharmacological agents. Natural dietary components, obtained from several fruits, vegetables, nuts and spices have drawn a considerable amount of attention due to their demonstrated ability to suppress carcinogenesis in animal models with some of these substances able to partially prevent or delay cancer formation in several high-risk populations.²⁵ Recent evidence has shown that dietary polyphenolic compounds including anthocyanidins from berries, catechins from green tea, curcumin from turmeric, genistein from soy, lycopene from tomatoes, and quercetin from red onions and apples are phytochemicals with significant anticancer properties.26, 27, 28, 29 A variety of bioactive food components have been shown to modify molecular targets involved in inflammation and redox signaling,30, 31 which are implicated in the development and progression of HCC. Supported by several in vitro assays and studies involving animal models as well as humans, evidence is emerging to support potential chemopreventive and chemotherapeutic effects of several phytochemicals in HCC.³² In this context, resveratrol, a naturally occurring antioxidant and antiinflammatory agent, has emerged as the lead promising molecule.

Resveratrol (3,4′,5-trihydroxy-trans-stilbene, Fig. 1) is a phytochemical found in several dietary sources, such as grapes, berries, peanuts as well as red wine. In nature, it functions as a fungicide produced by the plant itself to ward off potentially lethal organisms and counteract environmental stress.³³ Its value as a compound beneficial to human health is well documented.34, 35, 36 Perhaps, it is best known as the compound widely considered to be the agent responsible for the “French Paradox”, a phenomenon in which consumption of red wine is thought to reduce the incidence of heart disease.³⁷ Recent studies have indicated that besides red wine, rose and white wine could be cardioprotective as they also contain resveratrol albeit at lesser concentrations than that of red wine.³⁸ Resveratrol can prevent or slow the progression of a wide variety of inflammation-related illnesses, including cancer, neurodegenerative diseases, cardiovascular ailments, ischemic injury, and viral infections, as well as enhance stress resistance and extend the life span of various organisms.34, 35, 39, 40 An impressive body of experimental findings reveals multiple cellular targets of resveratrol affecting cellular proliferation and growth, apoptosis, inflammation, invasion, angiogenesis and metastasis.41, 42 During the past decade, the amount of research on this phytoalexin has soared, and there exists strong evidence which supports resveratrol as a potent chemopreventive and chemotherapeutic agent.

Jang et al.⁴³ first demonstrated the chemopreventive effects of resveratrol in inhibiting multi-stage carcinogenesis (e.g., initiation, promotion and progression). Subsequently, resveratrol has been shown to suppress proliferation of a wide variety of human tumor cells in vitro,44, 45, 46 which have led to numerous pre-clinical animal studies to evaluate the cancer chemopreventive and chemotherapeutic potential of resveratrol.47, 48 Several clinical trials, including one sponsored by the National Cancer Institute, are currently underway to investigate the use of both resveratrol and resveratrol-rich products, for prevention and treatment of colon cancer.⁴⁸ A significant amount of resveratrol accumulates and is retained in the liver.49, 50, 51, 52 Resveratrol has been shown to inhibit the hepatic carcinogen-activating enzymes, including cytochrome P450 1A1 (CYP1A1) and CYP3A/2 and induce hepatic phase 2 conjugating enzymes, namely NAD(P)H:quinine oxidoreductase, UDP-glucuronosyl transferase and glutathione S-transferase (GST) in vitro and in vivo.53, 54, 55, 56 The resultant effects of these enzyme modulation by resveratrol could be the reduced exposure of cells to carcinogens due to inhibition of carcinogen activation and/or elevated carcinogen detoxification and elimination. The most fascinating property of resveratrol, with regards to liver cancer, is its strong antiinflammatory⁵⁷ and antioxidant properties,⁵⁸ as both oxidative stress and inflammation have been strongly implicated in the occurrence and progression of HCC.16, 17, 19, 24 However, despite its great promise, the effects of resveratrol on liver cancer have not been systematically studied until recently. This review critically examines the current knowledge on the mechanism-based chemopreventive and chemotherapeutic potential of resveratrol in in vitro as well as pre-clinical animal models of HCC.