Carcinogenesis Advance Access published online on April 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh168
© 2004 by Oxford University Press
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1 Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan; Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
* To whom correspondence should be addressed. E-mail: mwachi{at}bio.titech.ac.jp.
Although (-)-epigallocatechin gallate (EGCG) has been reported to induce apoptosis in a variety of tumor cells, detailed mechanism remains to be explored. In the present study, we investigated the antitumor mechanism of EGCG by using human T-cell acute lymphoblastic leukemia Jurkat cells focusing on the involvement of reactive oxygen species, since we previously found that EGCG caused apoptotic cell death in osteoclastic cells mainly due to promotion of the reduction of Fe(III) to Fe(II) to trigger Fenton reaction, which affords hydroxyl radical from hydrogen peroxide [H2O2 + Fe(II) Key Words:
(-)-epigallocatechin gallate, Fenton reaction, hydrogen peroxide generation, apoptosis, Jurkat cell
Revised March 14, 2004
Accepted April 9, 2004
CANCER BIOLOGY
Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by (-)-epigallocatechin gallate
2 Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
3 Department of Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
4 Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Abstract 
•OH + OH- + Fe(III)]. EGCG (12.5-50 µM) decreased the viability of Jurkat cells and caused concomitant increase in cellular caspase-3 activity. Catalase and the Fe(II)-chelating reagent o-phenanthroline suppressed the EGCG effects, indicating involvements of both H2O2 and Fe(II) in the mechanism. Unexpectedly, epicatechin gallate (ECG), which has Fe(III)-reducing potency comparable to EGCG, failed to decrease viability of Jurkat cells, while epigallocatechin (EGC), which has low capacity to reduce Fe(III), showed cytotoxic effect similar to EGCG. These results suggest that, unlike in osteoclastic cells, a mechanism other than Fe(III) reduction plays a role in catechin-mediated Jurkat cell death. We found that EGCG causes an elevation of H2O2 levels in Jurkat cell culture, in cell-free culture medium and sodium phosphate buffer. Catechins with higher ability to produce H2O2 were more cytotoxic to Jurkat cells. Hydrogen peroxide itself exerted Fe(II)-dependent cytotoxicity. Among tumor and normal cell lines tested, cells exhibiting lower H2O2-eliminating activity were more sensitive to EGCG. From these findings, we propose the mechanism that cytotoxicity of catechins in certain tumor cells is due to their ability to produce H2O2 and that the resulting increase in H2O2 levels triggers Fe(II)-dependent formation of highly toxic hydroxyl radical, which in turn induces apoptotic cell death.
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