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Role of Curcumin on Tumor Angiogenesis in Hepatocellular Carcinoma

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Role of Curcumin on Tumor Angiogenesis in Hepatocellular Carcinoma Naresuan University Journal 2008; 16(3): 239-254 239 Role of Curcumin on Tumor Angiogenesis in Hepatocellular Carcinoma Pornphrom Chintana Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand. Corresponding author. E-mail address: [email protected] (P. Chintana) Received 14 July 2008; accepted 24 December 2008 Summary Hepatocellular carcinoma (HCC) is a malignant tumor characterized by active neovascularization. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor that regulates the HCC development. Overexpression of VEGF enhances the HCC tumor growth associated with increase of angiogenesis in the tumor, whereas suppression of VEGF attenuates the tumor growth. Similarly, the cyclooxygenase-2 (COX-2) expression stepwisely increases during hepatocarcinogenesis. Curcurmin has been shown to inhibit several angiogenic biomarkers including, VEGF and COX-2 expression. Therefore, curcumin could be used as a candidate for the combined drug treatment for HCC in the future. Keywords: Curcumin; Angiogenesis; Hepatocellular carcinoma; VEGF; COX-2 INTRODUCTION greater practical significance than non-selective cytotoxic therapies to control the tumor growth Hepatocellular carcinoma (HCC) is one of the and metastasis by targeting angiogenesis. Since, five most common cancers worldwide, with a many dietary and non-dietary phytochemicals do particularly high prevalence in Asian countries due not affect survival of normal cells and also possess to endemic hepatitis B virus infection (Parkin et al., anti-angiogenic as well as anti-tumorigenic 2001). In Thailand, it is the most common cause of activities, it could be a rationale approach to examine death in men (Vatanasapt et al., 2002). Surgery, their inhibitory effect on tumor angiogenesis. including transplantation, remains the only Therefore, selective targeting of tumor vasculature potentially curative modality for HCC, yet the by non-toxic phytochemicals could be a valuable recurrence rate for this particular cancer is high strategy for cancer control with reduced or no and long-term survival rate is rather poor. harmful side effects. Experimental and clinical data indicate that Many phytochemicals could have a tremendous human hepatocellular carcinoma tumor progression potential as anti-angiogenic agent including is associated with angiogenesis and that an green tea (catechins) (Tang et al., 2006), grape increase in microvascular density is associated (resvevatrol) (Lee et al., 2006), soy (isoflanones) with a poor prognosis. Angiogenesis plays a (Zhou et al., 1999), soy (genistein) (Shao et al., 1998) significant role in the aggressiveness of HCC and turmeric (curcumin) (Gururaj et al., 2002; (Pang & Poon, 2006; Semela & Dufour, 2004). A Singh et al., 1996; Yoysungnoen et al., 2006). better understanding of the mechanisms underlying These agents, which show anti-angiogenic effects HCC angiogenesis may provide a basis for a on tumors, act via different mechanisms to inhibit rational approach to develop an anti-angiogenic the angiogenic process by disrupt in various therapy in patients with HCC. components of tumor angiogenesis signaling Anti-angiogenic agents may have the following pathway, which starts from the tumor cells secreting theoretical advantages over cytotoxic chemotherapy: angiogenic factors and endings in the formation 1) the microvascular endothelial cells are of blood capillaries by endothelial cells. Among genetically stable with a low mutation rate 2) as these candidates, curcumin is the most important anti-angiogenic therapy targets the specific anti-angiogenic agent which has shown to inhibit immature characteristics of tumor vasculature, most step of tumor angiogenic process. which differs from normal quiescent vasculature, Curcumin (diferuloylmethane) which is a major has been demonstrated low toxicity in pre-clinical yellow pigment found in ground rhizome of studies; 3) endothelial cells are directly exposed Curcuma longa. It has possessed wide range of to blood borne agents, circumventing the problem pharmacological activities including anti-inflammation of drug delivery to tumor cells; this is a major (Guo et al., 2008; Jacob et al., 2007), anti-oxidant obstacle to conventional anticancer therapy (Sandur et al., 2007; Suryanarayana et al., 2007) (Pang & Poon, 2006). and anti-cancer (Kunnumakkara et al., 2008; In this regard, discovery of non-toxic Lin et al., 2007; Shankar et al., 2007; Yoysungnoen anti-angiogenic phytochemicals could have et al., 2008). Recently, it has been shown that the 240 Naresuan University Journal 2008; 16(3) anti-cancer property of curcumin is mediated in (PDGF), placental growth factor (PLGF), transforming part by its anti-angiogenic activity (Gururaj et al., growth factor (TGF)-b and others promotes the 2002; Singh et al., 1996; Yoysungnoen et al., sprouting of new vessels from nearby existing 2006). Therefore, the purpose of this review is vessels (Hanahan & Folkman, 1996; Jung et al., to discuss the possible role of curcumin, on tumor 2003). Additionally, hypoxia in the center of the angiogenesis, especially in hepatocellular carcinoma. growing tumors leads to intracellular stabilization of hypoxia-inducible factor (HIF)-1a, the key ANGIOGENESIS IN HEPATOCELLULAR transcription factor in hypoxic tissues, and induces CARCINOMA the expression of several hypoxia response genes, such as VEGF (Harris, 2002). On the other hand, Tumor angiogenesis is the proliferation of a hypoxia decreases anti-angiogenic factors like network of blood vessels that penetrates into thrombospondin-1 (Fox et al., 2001). Moreover, cancerous growths. Tumor angiogenesis actually genetic alterations in tumor suppressor genes starts with cancerous tumor cells releasing (loss of function) and oncogenes (gain of function) molecules that send signals to surrounding normal like p53, ras, myc, c-jun and others can upregulate host tissue. This signaling activates certain genes proangiogenic factors (Longo et al., 2002). Hepatitis B in the host tissue that, in turn, make proteins to virus X protein has also been shown to increase encourage growth of new blood vessels. Tumor the transcriptional activity and protein level growth and metastasis are angiogenic dependent. of HIF-1 and therefore promoting angiogenesis The development of tumor angiogenesis provides during hepatocarcinogenesis (Moon et al., 2004). two essential functions for the growth and Angiogenesis in HCC and other solid tumors metastasis of cancer. First, the vessels provide is based on the same fundamental principles a route for supply of nutrient and oxygen to sustain of activation, proliferation and migration of tumor growth, and excretion of metabolic waste. endothelial cells: secreted angiogenic factors Second, the neovessels provide access for tumor activate resting endothelial cells in adjacent blood cells to enter the circulation. Much of interest in vessels. Activated endothelial cells loosen angiogenesis comes from the notion that for tumors to interendothelial cell contacts and break down the grow beyond a critical size, they must recruit surrounding basement membrane and extracellular endothelial cells from the surrounding stroma to matrix by secreting proteases. Matrix proteins form their own endogenous microcirculation. This contain and sequester different angiogenic factors process is driven by the metabolic requirements such as VEGF, which are liberated after degradation of the rapidly growing tumor itself. Thus, during of the matrix and further stimulate endothelial tumor progression, two phases can be recognized: cells. These, then proliferate and migrate, involve a prevascular phase and a vascular phase. different integrins during migration, and finally The transition from the prevascular to the assemble to a tubular structure. Subsequent vascular phase is referred to as the "angiogenic formation of a lumen then leads to the formation switch". This angiogenic switch has been observed of a new blood vessel (Semela & Dufour, 2004). in different types of cancers. The angiogenic switch Pericytes are involved in the stabilization and depends on a net balance of positive and maturation of the newly formed vessel. Tumor negative angiogenic factors in the tumor (Hanahan vessels differ from normal vessels in many aspects & Folkman, 1996). It is now widely accepted that due to dysregulation of signaling pathways involved the angiogenic switch is "off" when the effect in angiogenesis and, therefore altered gene expression of angiogenic molecules is balanced by that of angiogenic factors. In comparison to normal of anti-angiogenic molecules, and is "on" when blood vessels, such newly formed tumor vessels are the net balance is tipped in favour of angiogenesis structurally and functionally abnormal. (Hanahan & Weinberg, 2000). In tumors, the By intravital fluorescent microscopy, our study switch to an angiogenic phenotype is known to demonstrated that there was a significant increase be critical for disease progression. Unless a tumor in the numbers of neocapillary density with can stimulate the formation of new blood vessels, the heterogeneous network in hepatocellular it remains restricted to a microscopic size. carcinoma (HepG2)-implanted nude mice in The switch to the angiogenic phenotype comparison to the controls (Yoysungnoen et al., involves a change in the local equilibrium between 2006). Particularly, we have noticed the changes activators and inhibitors of the growth of microvessels. of host arterioles, and
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