16160061

pubmed:Citation

13

Adriamycin is a widely used antitumor antibiotic, but its use has been limited by its cytotoxicity in both cardiomyocytes and non-cardiac tissues. While adriamycin's ability to redox cycle via one-electron transfer reactions and generate ROS is thought to promote cardiotoxicity, the mechanisms involved in non-cardiac tissue injury are not clear. Here we show that prolonged exposure (48 h) of human monocyte-derived macrophages to adriamycin at concentrations as low as 1 microM promotes caspase-independent cell death. Treatment of cells with scavengers of superoxide and peroxyl radicals blocked adriamycin-induced oxidation of dichlorodihydrofluorescein (DCFH) but did not prevent macrophage injury. Macrophages treated with either adriamycin or the thiol oxidant diamide showed elevated levels of glutathione disulfide and increased protein-S-glutathionylation prior to cell injury, indicating that thiol oxidation is involved in adriamycin-induced macrophage death. Furthermore, inhibition of glutathione reductase (GR) with 1,3-bis[2-chloroethyl]-1-nitrosourea or transfection of macrophages with small inhibitory RNA (siRNA) directed against GR or glutaredoxin (Grx) potentiated adriamycin-induced macrophage injury. Thus, both GR and Grx appear to play a crucial role in protecting macrophages from adriamycin-induced cell injury. These findings suggest a new mechanism for adriamycin-induced tissue injury whereby thiol oxidation, rather than one-electron redox cycling and ROS generation, mediates adriamycin-induced cell damage.

eng

IM

MEDLINE

1530-6860

Electronic

NLM

1866-8

pubmed-meshheading:16160061-Antineoplastic Agents, Alkylating, pubmed-meshheading:16160061-Carmustine, pubmed-meshheading:16160061-Diamide, pubmed-meshheading:16160061-Dose-Response Relationship, Drug, pubmed-meshheading:16160061-Doxorubicin, pubmed-meshheading:16160061-Electrons, pubmed-meshheading:16160061-Fluoresceins, pubmed-meshheading:16160061-Glutathione, pubmed-meshheading:16160061-Glutathione Disulfide, pubmed-meshheading:16160061-Glutathione Reductase, pubmed-meshheading:16160061-Humans, pubmed-meshheading:16160061-Macrophages, pubmed-meshheading:16160061-Models, Biological, pubmed-meshheading:16160061-Monocytes, pubmed-meshheading:16160061-Myocytes, Cardiac, pubmed-meshheading:16160061-Oxidation-Reduction, pubmed-meshheading:16160061-Oxidative Stress, pubmed-meshheading:16160061-Oxygen, pubmed-meshheading:16160061-RNA, Small Interfering, pubmed-meshheading:16160061-Reactive Oxygen Species, pubmed-meshheading:16160061-Sulfhydryl Compounds, pubmed-meshheading:16160061-Time Factors, pubmed-meshheading:16160061-Transfection, pubmed-meshheading:16160061-Wound Healing

A novel thiol oxidation-based mechanism for adriamycin-induced cell injury in human macrophages.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural