The anti-cancer drug, doxorubicin, causes oxidant stress-induced endothelial dysfunction.
Biochim Biophys Acta
; 1760(2): 267-71, 2006 Feb.
Article
en En
| MEDLINE
| ID: mdl-16337743
ABSTRACT
The anticancer drug doxorubicin (DOX) is toxic to target cells, but also causes endothelial dysfunction and edema, secondary to oxidative stress in the vascular wall. Thus, the mechanism of action of this drug may involve chemotoxicity to both cancer cells and to the endothelium. Indeed, we found that the permeability of monolayers of bovine pulmonary artery endothelial cells (BPAEC) to albumin was increased by approximately 10-fold above control, following 24-h exposure to clinically relevant concentrations of DOX (up to 1 microM). DOX also caused >4-fold increases in lactate dehydrogenase leakage and large decreases in ATP and reduced glutathione (GSH) in BPAECs, which paralleled the increases in endothelial permeability. A large part of the ATP loss could be attributed to DOX-induced hydrogen peroxide production which inhibited key thiol-enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate dehydrogenase (G6PDH). Depletion of reduced nicotinamide adenine dinucleotide phosphate (NADPH) appeared to be a major factor leading to DOX-induced GSH depletion. At low concentrations, the sulfhydryl reagent, iodoacetate (IA), inhibited GAPDH, caused a decrease in ATP and increased permeability, without inhibiting G6PDH or decreasing GSH. These results, coupled with those of previous work on a related quinone, menadione, suggest that depletion of either GSH or ATP may lead independently to endothelial dysfunction during chemotherapy, contributing to the cardiotoxicity and other systemic side-effects of the drug.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Doxorrubicina
/
Estrés Oxidativo
/
Endotelio
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos