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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
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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.

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