Antiangogenic Effect of Selected Phytochemicals
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ORIGINAL ARTICLES Department of Pharmacology1; Department of Experimental Medicine2, Faculty of Medicine, P.J. Safarik University, Kosice, Slovak Republic Antiangogenic effect of selected phytochemicals L. Varinska 1, L. Mirossay 1, G. Mojzisova 2, J. Mojzis 1 Received June 14, 2009, accepted July 10, 2009 Prof. Jan Mojzis, DVM, Ph.D., Department of Pharmacology, Faculty of Medicine, P.J. Safarik University, Trieda SNP 1, 04011 Kosice, Slovak Republic [email protected] Pharmazie 65: 57–63 (2010) doi: 10.1691/ph.2010.9667 Angiogenesis, the formation of new blood vessels from a preexisting vascular network is considered a key step in tumour growth, invasion, and metastasis. Recent studies show that several natural compounds inhibit angiogenesis and nowadays numerous bioactive plant compounds are tested for their antiangio- genic potential. This review examines current knowledge regarding the antiangiogenic potential of several phytochemicals, including polyphenols resveratrol and curcumin as well as miscellaneous compounds from garlic, Hypericum perforatum, Panax ginseng, Coptis chinensis and Rheum palmatum. 1. Introduction human health. An attractive hypothesis is that vegetables and fruits contain compounds that have protective effects, indepen- Angiogenesis, the development of new blood vessels, is a dent of those of known nutrients and micronutrients. Current fundamental physiological process that promotes embryonic interest is focused on beneficial health effects of dietary polyphe- development, tissue repair and fertility (Coultas et al. 2005). nols because these compounds have many biological activities Under pathological conditions, tumors stimulate angiogenesis, (for review, see Magrone et al. 2008; Pan and Ho 2008; Khan the formation of blood vessels, and take oxygen and nutrition et al. 2009). for rapid growth. Furthermore, tumors utilize blood vessels and As stated in our recent review (Mojziˇ sˇ et al. 2008), flavonoids lymph vessels for metastasis to other tissues and lymph nodes and their metabolic precursors, chalcones, possess very promis- (Hanahan and Folkman 1996; Fujita et al. 2008). ing antiangiogenic properties. However, other non-flavonoid Tumors can remain avascular and latent for years and acti- polyphenols, such as resveratrol and curcumin, may also signifi- vation of angiogenesis is a necessary condition for tumor cantly contribute to the antiangiogenic effect of polyphenol-rich development (Bergers and Benjamin 2003). It is known that plants. without blood supply the dimensions of a tumor nodule cannot exceed 2-3 mm3 due to hypoxia leading to death of tumor cells (Folkman 1995). Since a close relationship between tumor growth and angiogenesis had been clarified, various anti- angiogenic inhibitors for use in cancer treatment have been 2.1. Resveratrol studied. The best-known anti-angiogenic agents of this class One of the most widely investigated plant-derived bioactive are the vascular endothelial growth factor (VEGF) inhibitors compound is resveratrol (trans-3,5,4-trihydroxystilbene). It including bevacizumab that was approved for use as part of com- was first isolated in 1940 as a constituent of the roots of bination therapy with fluorouracil-based regimens for metastatic white hellebore (Veratrum grandiflorum) (Aggarwal et al. 2004). colorectal cancer (Shih and Lindley 2006). Resveratrol has been found in grapes, berries, peanuts and var- During the last 15 years, substantial effort has been dedicated to ious other fruits. Similarly to other polyphenolic compounds, identifying compounds that can be used to either prevent insur- it has been shown to affect tumorigenesis and tumor growth gence of primary tumors in subjects at high risk to develop (Nobili et al. 2009; Zhou et al. 2005; Fuggetta et al. 2006). cancer or prevent tumor relapse after surgical removal (Brem Recently, resveratrol has been found to inhibit angiogenesis, et al. 1993; Beckeen et al. 2000; Eder et al. 2002; Cox et al. but the mechanisms of its antiangiogenic activity has not been 2006; Kulke et al. 2006). At present, ongoing clinal trials are fully understood. focused on drugs with different mechanisms of action such as In 2001, Kimura and Okuda tested the effect of resveratrol blockade of matrix breakdown, direct inhibition of endothe- on the growth and metastasis to lung and tumor-induced neo- lial cells, blockade of activators of angiogenesis, inhibition of vascularization in Lewis lung carcinoma-bearing mice. They endothelial-specific integrin/survival signaling as well as drugs found that resveratrol, at doses of 2.5 and 10.0 mg/kg, signifi- with non-specific mechanism of action. cantly reduced tumor volume, its weight and metastasis to the lung in these animals. Resveratrol also inhibited tumor-induced neovascularization at the same doses in an in vivo model. More- 2. Antiangiogenic effects of phytochemicals over, resveratrol significantly inhibited the in vitro formation of Several hypotheses have been suggested to explain beneficial capillary-like tube formation by human umbilical vein endothe- effects of increased consumption of vegetables and fruits on lial cell (HUVECs). Pharmazie 65 (2010) 1 57 ORIGINAL ARTICLES Later, it was documented that resveratrol (40.0 mg/kg/day) Matrigel. In vivo, trans-resveratrol inhibited vascularization of exerted significant antitumor effects on experimentally-induced the chick embryo area vasculosa and murine melanoma B16 gliomas. Immunohistochemical analyses showed that the tumor growth and neovascularization. In all of the assays, cis- gliomas from resveratrol-treated rats had lower microvessel den- resveratrol exerted a limited effect. Furthermore, the authors sities than did control rats (Tseng et al. 2004; Chen et al. 2006). found that trans-resveratrol but not cis-resveratrol inhibited Furthermore, the antiangiogenic effect of resveratrol was exam- alphavbeta3 integrin-dependent endothelial cell adhesion and ined also on chick chorioallantoic membrane (CAM) model of the recruitment of enhanced green fluorescent protein-tagged angiogenesis. Mousa et al. (2005) found potent inhibitory effects beta3 integrin in focal adhesion contacts. of resveratrol on fibroblast growth factor-2 (FGF2) induced Reactive oxygen species (ROS) play a crucial role in vascu- angiogenesis and tumor growth. Resveratrol in a concentration- lar angiogenesis. Both in vitro and in vivo studies indicate that dependent manner also significantly promoted apoptosis in angiogenic response in vascular tissue is triggered by ROS sig- FGF2-stimulated endothelial cells by increasing p53 protein naling in a highly coordinated manner (Maulik 2002). Some production. Although the mechanisms of antiangiogenic activ- data indicate that scavenging properties of reseveratrol may ity of resveratrol are not clear, some mechanisms have been contribute to its anti-angiogenic effects. In a recent study, proposed. Lin and co-workers (2003) investigated the mechanisms by Hypoxia-inducible factor-1␣ (HIF-1␣) is overexpressed in many which resveratrol inhibits VEGF-induced angiogenic effects in human cancers and their metastases and is closely associated HUVECs. Exposure of HUVECs to 1 to 2.5 mol/l resvera- with a more aggressive tumor phenotype. Cao et al. (2004) inves- trol significantly blocked VEGF-mediated migration and tube tigated the effect of resveratrol on HIF-1␣ and VEGF expression formation but not cell proliferation. At the same concentra- in human ovarian cancer cells. They found that although resver- tions, resveratrol effectively abrogated VEGF-mediated tyrosine atrol did not affect HIF-1␣ mRNA levels, it did significantly phosphorylation of vascular endothelial (VE)-cadherin and its inhibit both basal-level and growth factor-induced HIF-1␣ pro- complex partner, beta-catenin. Src kinase assay showed that tein expression in the cells. Resveratrol also greatly inhibited VEGF-induced endogenous Src kinase activation was strongly VEGF expression. It was demonstrated that resveratrol inhibited inhibited by 1.0 and 2.5 M resveratrol. Reactive oxygen species HIF-1␣ and VEGF expression through multiple mechanisms. have been shown to be involved in VE-cadherin phosphorylation Resveratrol inhibited Akt and mitogen-activated protein kinase and its related functions. Detailed analysis showed that VEGF activation, inhibited insulin-like growth factor 1-induced HIF- caused an evident increase in peroxide which was strongly 1␣ and induced substantial HIF-1␣ protein degradation through attenuated by resveratrol. These data suggest that resveratrol the proteasome pathway. These results were confirmed by Zhang inhibition of VEGF-induced angiogenesis was mediated by and co-workers (2005) in human tongue squamous cell car- disruption of ROS-dependent Src kinase activation and the sub- cinomas and hepatoma cells. They documented a significant sequent VE-cadherin tyrosine phosphorylation. inhibition of both basal level and hypoxia-induced HIF-1␣ Encouraging results of in vitro/in vivo studies of antiangiogenic protein accumulation in cancer cells. Pretreatment of cancer effects of resveratrol led to the synthesis of novel derivatives of cells with resveratrol significantly reduced hypoxia-induced resveratrol. Kimura et al. (2008) examined the antiangiogenic VEGF promoter activities and VEGF expression. In addition, effects of 21 synthetic and/or natural stilbenes. Among these resveratrol markedly inhibited hypoxia-mediated activation of stilbenes, 2,3-, 3,4-, and 4,4-dihydroxystilbene inhibited pro- extracellular signal-regulated kinase 1/2 (Erk 1/2)