The anti-cancer drug, doxorubicin, causes oxidant stress-induced endothelial dysfunction.
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.
Wolf
Matthew B
MB
Department of Pharmacology, University of South Carolina School of Medicine, Columbia, SC 29208, USA. wolf@med.sc.edu
Baynes
John W
JW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects; D004727:Endothelium / Q000187:drug effects* / Q000503:physiopathology*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007461:Iodoacetates / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects
D007461:Iodoacetates; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005978:Glutathione