Mitochondria-independent morphological and biochemical apoptotic alterations promoted by the anti-tumor agent bleomycin in Saccharomyces cerevisiae.
Bleomycin is a highly potent cytotoxic and genotoxic agent used in the chemotherapy of various types of tumors. It is a radiomimetic anticancer drug that produces single- and double-stranded DNA breaks in a catalytic way. Using Saccharomyces cerevisiae as a model system, we show that when a high amount of bleomycin molecules is internalized (100 micromol/L), morphological changes identical to those usually associated with apoptosis, i.e., a sub-G1 region peak, chromatin condensation, and very rapid DNA fragmentation into oligonucleosomal-sized fragments, are observed. The known bleomycin inhibitors cobalt and EDTA were able to prevent bleomycin nucleasic activity and thus apoptotic cell death. However, both oligomycin, a potent inhibitor of the mitochondrial F0F1-ATPase, and antimycin, a drug affecting mitochondria respiration, were unable to prevent the bleomycin-induced apoptotic-like cell death. These results suggest that high bleomycin concentrations induce an apoptosis-like mitochondria-independent cell death in yeast.
Aouida
Mustapha
M
Laboratoire de Vectorologie et Transfert de Gènes, UMR 8121 CNRS, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cédex, France. maouida.hmr@ssss.gouv.qc.ca
Mekid
Halima
H
Belhadj
Omrane
O
Mir
Lluis M
LM
Tounekti
Omar
O
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001761:Bleomycin / Q000494:pharmacology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation; D004492:Edetic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects*; D009840:Oligomycins / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D009840:Oligomycins; D001761:Bleomycin; C032456:antimycin; D000968:Antimycin A; D004492:Edetic Acid