The ratio of single- to double-strand DNA breaks and their absolute values determine cell death pathway

Bleomycin is a cytotoxic antibiotic that generates DNA double-strand breaks (DSB) and DNA single-strand breaks (SSB). It is possible to introduce known quantities of bleomycin molecules into cells. Low amounts kill the cells by a slow process termed mitotic cell death, while high amounts produce a f...

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Bibliographic Details
Published in:British journal of cancer 2001-05, Vol.84 (9), p.1272-1279
Main Authors: Tounekti, O, Kenani, A, Foray, N, Orlowski, S, Mir, L M
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic agents
Apoptosis
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Bleomycin - analogs & derivatives
Bleomycin - pharmacology
Cancer Research
Cell death
Cricetinae
Cricetulus
DNA Damage
DNA, Single-Stranded - genetics
Dose-Response Relationship, Drug
Drug Resistance
Epidemiology
Fibroblasts
General aspects
Medical sciences
Mitosis
Molecular Medicine
Oncology
Pharmacology. Drug treatments
Regular
regular-article
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Summary:Bleomycin is a cytotoxic antibiotic that generates DNA double-strand breaks (DSB) and DNA single-strand breaks (SSB). It is possible to introduce known quantities of bleomycin molecules into cells. Low amounts kill the cells by a slow process termed mitotic cell death, while high amounts produce a fast process that has been termed pseudoapoptosis. We previously showed that these types of cell death are a direct consequence of the DSB generated by bleomycin. Here, we use deglyco-bleomycin, a bleomycin derivative lacking the carbohydrate moiety. Although this molecule performs the same nucleophilic attacks on DNA as bleomycin, we show that deglyco-bleomycin is at least 100 times less toxic to Chinese hamster fibroblasts than bleomycin. In fact, deglyco-bleomycin treatment results in apoptosis induction. In contrast, however, deglyco-bleomycin was found to generate almost exclusively SSB. Our results suggest that more than 150 000 SSB per cell are required to trigger apoptosis in Chinese hamster fibroblasts and that SSB are 300 times less toxic than DSB. Taken together with previous studies on bleomycin, our data demonstrates that cells can die by apoptosis, mitotic cell death, or pseudoapoptosis, depending on the number of DNA breaks and on the ratio of SSB to DSB. © 2001 Cancer Research Campaign http://www.bjcancer.com
ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1054/bjoc.2001.1786