Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/18/2004
Publication Date: 12/4/2004
Citation: Zhou, Y., Kim, Y., Li, X., Baerson, S.R., Agarwal, A.K., Hodges, T.W., Ferreira, D., Nagle, D.G. 2004. Hypoxia-inducible factor-1 activation by (-)- epicatechin gallate: potential adverse effects of cancer chemoprevention with high-dose green tea extract. Journal of Natural Products. 67:2063-2069. Interpretive Summary: Plant natural products have for many years been viewed as an important source for new anticancer treatments. Recently, extracts from the plant Camillia sinesis, which is the source for green and black tea leaves, have been touted as a potential chemopreventative treatment. Tea leaves are a rich source of chemicals known as catechins, which have been proposed to be responsible for the anticancer properties of Camillia sinesis extracts. Although laboratory and some epidemiological studies have strongly supported the benefits of Camillia sinesis extracts, other epidemiological studies have failed to show a clear correlation with chemoprevention. In this study it is demonstrated that certain molecular targets associated with advanced tumorogenesis are actually stimulated by one specific catechin found in green tea, known as (-)-epicatechin-3-gallate (ECG). ECG was found to increase the levels of HIF-1alpha, an important regulatory protein which activates a network of genes that promote tumor development in humans. Although ECG is not known to be carcinogenic, it may promote the growth of tumors once they have been initiated. Thus, the utility of Camillia sinesis extracts as a chemopreventative treatment may be undermined by the presence of compounds such as ECG which may actually help promote tumor progression.
Technical Abstract: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that induces oxygen-regulated genes in response to reduced oxygen conditions (hypoxia). Expression of the oxygen regulated HIF-1alpha subunit correlates positively with advanced disease stages and poor prognosis in cancer patients. Green tea catechins are polyphenolic compounds believed to be responsible for the cancer chemopreventive activities of green tea. We have found that (-)-epicatechin-3-gallate (ECG), one of the major green tea catechins, strongly activates HIF-1 in T47D human breast carcinoma cells. Among the green tea catechins tested, ECG demonstrated the strongest HIF-1 inducing activity and the other 3-gallate moiety containing catechin (-)-epigallocatechin-3-gallate (EGCG) was significantly less active. However, in the in vitro system studied, EGCG is relatively unstable. The catechin ECG also increases the expression of HIF-1 target genes including glut-1, VEGF, and p21waf1/cip1. In T47D cells, ECG induces nuclear HIF-1alpha protein without affecting HIF-1alpha mRNA. Further, both the induction of HIF-1alpha protein and activation of HIF-1 by ECG can be blocked by iron and ascorbate, suggesting that one mechanism used by ECG to activate HIF-1 is through the chelation of iron. In summary, our results suggest that cancer chemoprevention with high dose green tea extracts may exert the opposite effect - promoting tumor cell survival through HIF-1 activation.