Unravelling green tea's mechanisms of action: more than meets the eye.

After water, tea is the most popular beverage and is consumed by two thirds of the world’s population. Three types of tea are available; they vary in the processes of drying and fermentation. Besides black tea, which is the most prevalent form (78%), green tea (20%) and oolong (2%) are produced. The tea plant Camellia sinensis is native to South China and was brought to Japan by the Zen priest Eisai. Green tea in particular is an essential part of daily life in China, Japan, and India. Green tea is obtained by steaming freshly harvested tea leaves, thus causing inactivation of enzymes that initiate the fermentation process. This yields a dry and stable product that contains most of the polyphenols and gives green tea its typical color and taste (Bachrach and Wang, 2002). Green tea is rich in polyphenolic compounds, which account for a third of the dry weight of the leaves; the most prominently components are flavonols, commonly known as catechins (Balentine et al., 1997). These include epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin3-gallate (EGCG). For a long time, green tea was preferred as a beverage because of its attractive flavor and taste. But the scientific community and the popular press have recently pondered that there might be beneficial properties of green tea. Consumption has been associated with anti-inflammatory, antioxidative, antimutagenic, and anticarcinogenic effects (Benelli et al., 2002; Weisburger and Chung, 2002). In general, plants used for nutrition or for medical therapy contain a series of antioxidants (e.g., among others, vitamin C, vitamin E, -carotene, polyphenols, or selenium) that act as potent radical scavengers. These compounds are thought to be responsible for many beneficial effects, particularly in inflammatory diseases but also in cancer prevention. The alteration of the redox-state of the cell by antioxidants also triggers fine-tuned changes in signaling pathways and subsequent gene expression (Chen et al., 2002; Pfeilschifter et al., 2003). Tea polyphenols have shown cytostatic properties in several tumor models. In particular, green tea catechins can act at different sites. One facet of the antitumor activities exerted by EGCG seems to be attributable to blocking of the EGF receptor (Liang et al., 1997) and the platelet-derived growth factor receptor (Sachinidis et al., 2000), which can inhibit the growth factor-induced activation of activator protein 1, a transcription factor critically involved in the action of various growth factors and cytokines. Additionally, a recent study has demonstrated an EGCG-dependent inhibition of focal adhesion kinase activity, indicating a negative interference of green tea with cell adhesion and cell movement processes (Liu et al., 2001). Most interestingly, mice that were infused with either green tea or pure EGCG showed a reduced angiogenic response to vascular endothelial-derived growth factor, a key regulator of angiogenesis, as reflected by a dose-dependent reduction of vessel formation (Cao and Cao, 1999). Proteasedependent degradation of extracellular matrix components is one of the main prerequisites of metastasis. Importantly, in this context, many studies have identified the group of serine and metalloproteinases as downstream targets of antimetastatic activities exerted by green tea polyphenols. Indeed, EGCG was described to inhibit the urokinase-type plasminogen activator, a major activator of the matrix metalloproteinase (MMP) cascade, although the effective EGCG concentration (in the millimolar range) markedly exceeds plasma levels measured in vivo (Cao and Cao, 1999). In contrast to the urokinase-type plasminogen activator, the inhibition of MMP-2 and MMP-9 gelatinases by EGCG, which results in a significant reduction of the invasive behavior of gelatinaseexpressing cancer cells, could be observed with concentrations an order of magnitude lower than those reported for the inhibition of urokinase (Benelli et al., 2002). Clinically, high gelatinase expression correlates with high invasive potential and tumor spread and therefore seems to be a negative prognostic factor in many cancers. The proposed mechanisms of MMP inhibition by EGCG are diverse, ranging from noncom-