Implication of radical oxygen species in ceramide generation, c-Jun N-terminal kinase activation and apoptosis induced by daunorubicin

V Mansat-de Mas; C Bezombes; A Quillet-Mary; A Bettaïeb; A D D'orgeix; G Laurent; J P Jaffrézou

doi:10.1124/mol.56.5.867

Implication of radical oxygen species in ceramide generation, c-Jun N-terminal kinase activation and apoptosis induced by daunorubicin

Mol Pharmacol. 1999 Nov;56(5):867-74. doi: 10.1124/mol.56.5.867.

Authors

V Mansat-de Mas¹, C Bezombes, A Quillet-Mary, A Bettaïeb, A D D'orgeix, G Laurent, J P Jaffrézou

Affiliation

¹ Institut National de la Sante et de la Recherche Medicale E9910, Institut Claudius Régaud, Toulouse, France.

PMID: 10531389
DOI: 10.1124/mol.56.5.867

Abstract

Anthracyclines such as daunorubicin (DNR) generate radical oxygen species (ROS), which account, at least in part, for their cytotoxic effect. We observed that early ceramide generation (within 6-10 min) through neutral sphingomyelinase stimulation was inhibitable by the antioxidants N-acetylcysteine and pyrrolidine dithiocarbamate, which led to a decrease in apoptosis (>95% decrease in DNA fragmentation after 6 h). Furthermore, we observed that DNR triggers the c-Jun N-terminal kinase (JNK) and the transcription factor activated protein-1 through an antioxidant-inhibitable mechanism. Treatment of U937 cells with cell-permeant ceramides induced both an increase in ROS generation and JNK activation, and apoptosis, all of which were antioxidant-sensitive. In conclusion, DNR-triggered apoptosis implicates a ceramide-mediated, ROS-dependent JNK and activated protein-1 activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcysteine / pharmacology
Antineoplastic Agents / pharmacology*
Antioxidants / pharmacology
Apoptosis*
Ceramides / biosynthesis*
Daunorubicin / pharmacology*
Drug Interactions
Electron Transport / drug effects
Enzyme Activation
Free Radical Scavengers / antagonists & inhibitors
Free Radical Scavengers / pharmacology
Humans
Hydrogen Peroxide / metabolism
JNK Mitogen-Activated Protein Kinases
Mitochondria / drug effects
Mitochondria / metabolism
Mitogen-Activated Protein Kinases / metabolism*
Pyrrolidines / pharmacology
Reactive Oxygen Species / metabolism*
Sphingomyelin Phosphodiesterase / metabolism
Thiocarbamates / pharmacology
Transcription Factor AP-1 / metabolism
U937 Cells

Substances

Antineoplastic Agents
Antioxidants
Ceramides
Free Radical Scavengers
Pyrrolidines
Reactive Oxygen Species
Thiocarbamates
Transcription Factor AP-1
pyrrolidine dithiocarbamic acid
Hydrogen Peroxide
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Sphingomyelin Phosphodiesterase
Acetylcysteine
Daunorubicin