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J. Biol. Chem., Vol. 279, Issue 7, 6056-6064, February 13, 2004

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Lipid Antioxidant, Etoposide, Inhibits Phosphatidylserine Externalization and Macrophage Clearance of Apoptotic Cells by Preventing Phosphatidylserine Oxidation^*

Yulia Y. Tyurina, F. Behice Serinkan, Vladimir A. Tyurin, Vidisha Kini, Jack C. Yalowich, Alan J. Schroit¶, Bengt Fadeel||, and Valerian E. Kagan**

From the Departments of Environmental and Occupational Health and Pharmacology, ^**Cancer Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, ^¶Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and ^||Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden

Apoptosis is associated with the externalization of phosphatidylserine (PS) in the plasma membrane and subsequent recognition of PS by specific macrophage receptors. Selective oxidation of PS precedes its externalization/recognition and is essential for the PS-dependent engulfment of apoptotic cells. Because etoposide is a potent and selective lipid antioxidant that does not block thiol oxidation, we hypothesized that it may affect PS externalization/recognition without affecting other features of the apoptotic program. We demonstrate herein that etoposide induced apoptosis in HL-60 cells without the concomitant peroxidation of PS and other phospholipids. HL-60 cells also failed to externalize PS in response to etoposide treatment. In contrast, oxidant (H₂O₂)-induced apoptosis was accompanied by PS externalization and oxidation of different phospholipids, including PS. Etoposide potentiated H₂O₂-induced apoptosis but completely blocked H₂O₂-induced PS oxidation. Etoposide also inhibited PS externalization as well as phagocytosis of apoptotic cells by J774A.1 macrophages. Integration of exogenous PS or a mixture of PS with oxidized PS in etoposide-treated HL-60 cells reconstituted the recognition of these cells by macrophages. The current data demonstrate that lipid antioxidants, capable of preventing PS peroxidation, can block PS externalization and phagocytosis of apoptotic cells by macrophages and hence dissociate PS-dependent signaling from the final common pathway for apoptosis.

Received for publication, September 8, 2003 , and in revised form, November 13, 2003.

^* This work was supported by National Institutes of Health Grants HL70755, CA90787, and GM64610 and the Swedish Society for Medical Research (to B. F.). J. C. Y. has a significant equity interest, as defined by the U. S. Public Health Service, in Bristol-Myers Squibb Co., a manufacturer of etoposide, used in this research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260. Tel.: 412-383-2136; Fax: 412-383-2123; E-mail: kagan{at}pitt.edu.

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