Deglycosylated bleomycin induces apoptosis in lymphoma cell via c-jun NH2-terminal kinase but not reactive oxygen species.
Bleomycin (BLM) has demonstrated potent activity in treating malignant lymphomas but its therapeutic efficacy is hampered by induction of lung fibrosis. This side effect is related to the ability of the drug to generate reactive oxygen species in lung cells. In the present study, we evaluated the consequences of deglycosylation of BLM in term of cytotoxic activity and generation of reactive oxygen species. When tested on U937 human lymphoma cells, both compounds generated a typical apoptotic phenotype. Cell death induction was associated with Bax oligomerization, dissipation of the mitochondrial membrane potential, release of cytochrome c, caspase activation, chromatin condensation and internucleosomal degradation. Whereas both reactive oxygen species and c-jun NH(2)-terminal kinase (JNK) inhibitors prevented BLM-induced U937 cell death, only JNK inhibition prevented deglycosylated BLM-mediated cell death. Both compounds induced clustering of TRAIL receptors (DR4 and DR5) and Fas at the cell surface but neither a chimeric soluble DR5 receptor that inhibits TRAIL-induced cell death nor a dominant negative version of the adaptor molecule Fas-associated death domain prevented BLM-induced cytotoxicity. These observations indicate that deglycosylation of BLM does not impair the ability of the drug to trigger cell death through activation of the intrinsic pathway but prevents induction of reactive oxygen species. This observation suggests that deglycosylated BLM could exhibit less toxic side effects and could warrant its use in clinic.
Souhir
Brahim
B
Laboratory of Biochemistry, Faculty of Medicine, 5019 Monastir, Tunisia.
Laurent
Prévotat
P
Sonia
Yatouji
Y
Delphine
Mérino
M
Marion
Cortier
C
Cédric
Rébé
R
Olivier
Micheau
M
Abderraouf
Kenani
K
Ali
Bettaieb
B
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008223:Lymphoma / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D020298:U937 Cells