NDLI: Doxorubicin-induced Apoptosis in Endothelial Cells and Cardiomyocytes Is Ameliorated by Nitrone Spin Traps and Ebselen ROLE OF REACTIVE OXYGEN AND NITROGEN SPECIES

Content Provider	Journal of Biological Chemistry (JBC)
Author	Kotamraju, Srigiridhar Konorev, Eugene A. Joseph, Joy Kalyanaraman, B.
Abstract	Doxorubicin (DOX) is a broad spectrum anthracycline antibiotic used to treat a variety of cancers. Redox activation of DOX to form reactive oxygen species has been implicated in DOX-induced cardiotoxicity. In this work we investigated DOX-induced apoptosis in cultured bovine aortic endothelial cells and cardiomyocytes isolated from adult rat heart. Exposure of bovine aortic endothelial cells or myocytes to submicromolar levels of DOX induced significant apoptosis as measured by DNA fragmentation and terminal deoxynucleotidyltransferase-mediated nick-end labeling assays. Pretreatment of cells with 100 μm nitrone spin traps, N-tert-butyl-α-phenylnitrone (PBN) or α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) dramatically inhibited DOX-induced apoptosis. Ebselen (20–50 μm), a glutathione peroxidase mimetic, also significantly inhibited apoptosis. DOX (0.5–1 μm) inactivated mitochondrial complex I by a superoxide-dependent mechanism. PBN (100 μm), POBN (100 μm), and ebselen (50 μm) restored complex I activity. These compounds also inhibited DOX-induced caspase-3 activation and cytochrome crelease. PBN and ebselen also restored glutathione levels in DOX-treated cells. We conclude that nitrone spin traps and ebselen inhibit the DOX-induced apoptotic signaling mechanism and that this antiapoptotic mechanism may be linked in part to the inhibition in formation or scavenging of hydrogen peroxide. Therapeutic strategies to mitigate DOX cardiotoxicity should be reexamined in light of these emerging antiapoptotic mechanisms of antioxidants.
Related Links	http://www.jbc.org/content/275/43/33585.abstract
Ending Page	33592
Starting Page	33585
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	43
Volume Number	275
DOI	10.1074/jbc.M003890200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2000-10-27
Access Restriction	Open
Subject Keyword	Doxorubicin (DOX) Bovine aortic endothelial cells (BAEC) Acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO) NG-nitro-l-arginine methyl ester (l-NAME) Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) N-tert-butyl-α-phenylnitrone (PBN) Α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) Terminal deoxynucleotidyltransferase-mediated nick-end labeling (assay) (TUNEL) N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-VAD- fmk) Phosphate-buffered saline (PBS) 1,4-piperazinediethanesulfonic acid (PIPES) Tris-buffered saline (TBS) Fetal bovine serum (FBS) Dichlorofluorescein (DCF) MECHANISMS OF SIGNAL TRANSDUCTION
Alternative Title	Doxorubicin-induced Apoptosis in Endothelial Cells and Cardiomyocytes Is Ameliorated by Nitrone Spin Traps and Ebselen
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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