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J. Biol. Chem., Vol. 282, Issue 18, 13468-13476, May 4, 2007

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Cyanidin-3-rutinoside, a Natural Polyphenol Antioxidant, Selectively Kills Leukemic Cells by Induction of Oxidative Stress^*

Rentian Feng, Hong-Min Ni, Shiow Y. Wang, Irina L. Tourkova, Michael R. Shurin, Hisashi Harada^¶, and Xiao-Ming Yin¹

From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, The Fruit Laboratory, Beltsville Agricultural Research Center, United States Department of Agriculture, Beltsville, Maryland 20705, and the ^¶Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298

Anthocyanins are a group of naturally occurring phenolic compounds widely available in fruits and vegetables in human diets. They have broad biological activities including anti-mutagenesis and anticarcinogenesis, which are generally attributed to their antioxidant activities. We studied the effects and the mechanisms of the most common type of anthocyanins, cyanidin-3-rutinoside, in several leukemia and lymphoma cell lines. We found that cyanidin-3-rutinoside extracted and purified from the black raspberry cultivar Jewel induced apoptosis in HL-60 cells in a dose- and time-dependent manner. Paradoxically, this compound induced the accumulation of peroxides, which are involved in the induction of apoptosis in HL-60 cells. In addition, cyanidin-3-rutinoside treatment resulted in reactive oxygen species (ROS)-dependent activation of p38 MAPK and JNK, which contributed to cell death by activating the mitochondrial pathway mediated by Bim. Down-regulation of Bim or overexpression of Bcl-2 or Bcl-x_L considerably blocked apoptosis. Notably, cyanidin-3-rutinoside treatment did not lead to increased ROS accumulation in normal human peripheral blood mononuclear cells and had no cytotoxic effects on these cells. These results indicate that cyanidin-3-rutinoside has the potential to be used in leukemia therapy with the advantages of being widely available and selective against tumors.

Received for publication, November 15, 2006 , and in revised form, February 23, 2007.

^* 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.

¹ Supported in part by National Institutes of Health Grants CA83817, CA111456, and NS045252. To whom correspondence should be addressed: Dept. of Pathology, University of Pittsburgh School of Medicine, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-8436; Fax: 412-684-9564; E-mail: xmyin{at}pitt.edu.

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