DNA damage and cytotoxicity induced by β -lapachone: relation to poly(ADP-ribose) polymerase inhibition
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, ISSN: 0027-5107, Vol: 401, Issue: 1, Page: 55-63
1998
- 34Citations
- 15Captures
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Metrics Details
- Citations34
- Citation Indexes34
- 34
- CrossRef18
- Captures15
- Readers15
- 15
Article Description
β -lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione) was previously shown to enhance the lethality of X-rays and radiomimetic agents and its radiosensitizing role in mammalian cells was attributed to a possible interference with topoisomerase I activity. Furthermore, β -lapachone alone was found to induce chromosomal damage in Chinese hamster ovary (CHO) cells. The aim of the present study was to further elucidate the possible mechanisms by which β -lapachone exerts its genotoxic action in cultured mammalian cells. Flow cytometry analysis of β -lapachone-treated CHO cells indicated a selective cytotoxic effect upon S phase of the cell cycle. β -lapachone produced DNA strand breaks as determined by alkaline elution assay; alkaline elution profiles from treated cells showed a bimodal dose-response pattern, with a threshold dose above which a massive dose-independent DNA degradation was observed. Furthermore, β -lapachone increased the capacity of crude CHO cellular extracts to unwind supercoiled plasmid DNA, while significantly inhibiting in vitro poly(ADP-ribose) polymerase (PARP). These results suggest that damage induction is probably mediated by the interaction between β -lapachone and cellular enzymatic function(s), rather than reflecting a direct action on the DNA. We suggest that the inhibition of PARP plays a central role in the complex biological effects induced by β -lapachone in CHO cells.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S002751079700273X; http://dx.doi.org/10.1016/s0027-5107(97)00273-x; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0032486082&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/9639674; https://linkinghub.elsevier.com/retrieve/pii/S002751079700273X; http://linkinghub.elsevier.com/retrieve/pii/S002751079700273X; http://api.elsevier.com/content/article/PII:S002751079700273X?httpAccept=text/xml; http://api.elsevier.com/content/article/PII:S002751079700273X?httpAccept=text/plain; http://dx.doi.org/10.1016/s0027-5107%2897%2900273-x; https://dx.doi.org/10.1016/s0027-5107%2897%2900273-x
Elsevier BV
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