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Originally published In Press as doi:10.1074/jbc.M106829200 on September 28, 2001

J. Biol. Chem., Vol. 276, Issue 50, 47266-47276, December 14, 2001
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Doxorubicin-induced Apoptosis Is Associated with Increased Transcription of Endothelial Nitric-oxide Synthase
EFFECT OF ANTIAPOPTOTIC ANTIOXIDANTS AND CALCIUM*

Shasi V. Kalivendi, Srigiridhar Kotamraju, Hongtao Zhao, Joy Joseph, and B. KalyanaramanDagger

From the Biophysics Research Institute and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

The clinical efficacy of the antitumor antibiotic drug doxorubicin (DOX) is severely limited by its dose-limiting cardiotoxicity in cancer patients. DOX-induced generation of reactive oxygen species was proposed to be a major mechanism of its cardiotoxicity. Previously, we showed that DOX undergoes a reductive activation at the reductase domain of endothelial nitric-oxide synthase (eNOS) forming the semiquinone and superoxide (Vásquez-Vivar, J., Martasek, P., Hogg, N., Masters, B. S. S., Pritchard, K. A., Jr., and Kalyanaraman, B. (1997) Biochemistry 36, 11293-11297). In this report, we provide evidence for DOX-induced increase in eNOS transcription and protein expression in bovine aortic endothelial cells (BAEC). We propose that DOX-induced hydrogen peroxide formation is responsible for the increased transcription of eNOS. BAEC treated with antisense eNOS oligonucleotide inhibits DOX-induced endothelial apoptosis. Treatment with antioxidants restored the levels of antiapoptotic proteins (Hsp70 and Bcl-2) in DOX-treated BAEC. DOX-induced intracellular oxidative stress, as measured by oxidation of dichlorodihydrofluorescein diacetate to dichlorofluorescein and hydroethidium to ethidium, was inhibited by antisense eNOS oligonucleotide and antioxidant treatment. Furthermore, antiapoptotic antioxidants (e.g. FeTBAP, ebselen, and alpha -phenyl-tert-butyl nitrone) inhibited DOX-induced eNOS transcription. We conclude that DOX-induced apoptosis is linked to the redox activation of DOX by eNOS.

* This work was supported by National Institutes of Health Grants RR01008 and CA77822.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Biophysics Research Institute, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel.: 414-456-4035; Fax: 414-456-6512; E-mail: balarama@mcw.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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