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Article

Hypoxia-Inducible Factor-1 Activation by (−)-Epicatechin Gallate: Potential Adverse Effects of Cancer Chemoprevention with High-Dose Green Tea Extracts

Supporting Info

Yu-Dong Zhou,*^†^‡ Yong-Pil Kim,^‡ Xing-Cong Li,^† Scott R. Baerson,^§ Ameeta K. Agarwal,^† Tyler W. Hodges,^‡ Daneel Ferreira,^‡ and Dale G. Nagle*^‡

National Center for Natural Products Research and Department of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, P.O. Box 1848, University of Mississippi, University, Mississippi 38677, and U.S. Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, P.O. Box 8048, University, Mississippi 38677

J. Nat. Prod., 2004, 67 (12), pp 2063–2069

DOI: 10.1021/np040140c

Publication Date (Web): December 4, 2004

To whom correspondence should be addressed. (Y.-D.Z.) Tel: (662) 915-1005. Fax: (662) 915-7062. E-mail: ydzhou@olemiss.edu. (D.G.N.) Tel: (662) 915-7026. Fax: (662) 915-6975. E-mail: dnagle@olemiss.edu.

†

National Center for Natural Products Research, University of Mississippi.

‡

Department of Pharmacognosy, University of Mississippi.

USDA, ARS-NPURU.

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-1α subunit correlates positively with advanced disease stages and poor prognosis in cancer patients. Green tea catechins are believed to be responsible for the cancer chemopreventive activities of green tea. We found that (−)-epicatechin-3-gallate (ECG, 1), one of the major green tea catechins, strongly activates HIF-1 in T47D human breast carcinoma cells. Among the green tea catechins tested, 1 demonstrated the strongest HIF-1-inducing activity, while (−)-epigallocatechin-3-gallate (EGCG, 2) was significantly less active. However, 2 is relatively unstable in the in vitro system studied. Compound 1 also increases the expression of HIF-1 target genes including GLUT-1, VEGF, and CDKN1A. In T47D cells, 1 induces nuclear HIF-1α protein without affecting HIF-1α mRNA. Both the induction of HIF-1α protein and activation of HIF-1 by 1 can be blocked by iron and ascorbate, indicating that 1 may activate HIF-1 through the chelation of iron. These results suggest that intended cancer chemoprevention with high-dose green tea extracts may be compromised, by the ability of tea catechins to promote tumor cell survival pathways associated with HIF-1 activation.

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