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Green Tea Component, Catechin, Induces Apoptosis of Human Malignant B Cells via Production of Reactive Oxygen Species

Authors' Affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Requests for reprints: Masahiro Kizaki, Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: 81-3-5363-3785; Fax: 81-3-3353-3515; E-mail: makizaki{at}sc.itc.keio.ac.jp.

Purpose: Green tea polyphenol, (–)-epigallocatechin-3-gallate, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of (–)-epigallocatechin-3-gallate as a novel therapeutic agent for the patients with B-cell malignancies including multiple myeloma.

Experimental Design: We investigated the effects of (–)-epigallocatechin-3-gallate on the induction of apoptosis in HS-sultan as well as myeloma cells in vitro and further examined the molecular mechanisms of (–)-epigallocatechin-3-gallate-induced apoptosis.

Results: (–)-Epigallocatechin-3-gallate rapidly induced apoptotic cell death in various malignant B-cell lines in a dose- and time-dependent manner. (–)-Epigallocatechin-3-gallate-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials (_m); the release of cytochrome c, Smac/DIABLO, and AIF from mitochondria into the cytosol; and the activation of caspase-3 and caspase-9. Elevation of intracellular reactive oxygen species (ROS) production was also shown during (–)-epigallocatechin-3-gallate-induced apoptosis of HS-sultan and RPMI8226 cells as well as fresh myeloma cells. Antioxidant, catalase, and Mn superoxide dismutase significantly reduced ROS production and (–)-epigallocatechin-3-gallate-induced apoptosis, suggesting that ROS plays a key role in (–)-epigallocatechin-3-gallate-induced apoptosis in B cells. Furthermore, a combination with arsenic trioxide (As₂O₃) and (–)-epigallocatechin-3-gallate significantly enhanced induction of apoptosis compared with As₂O₃ alone via decreased intracellular reduced glutathione levels and increased production of ROS.

Conclusions: (–)-Epigallocatechin-3-gallate has potential as a novel therapeutic agent for patients with B-cell malignancies including multiple myeloma via induction of apoptosis mediated by modification of the redox system. In addition, (–)-epigallocatechin-3-gallate enhanced As₂O₃-induced apoptosis in human multiple myeloma cells.

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