DNA damage and cytotoxicity induced by beta-lapachone: relation to poly (ADP-ribose) polymerase inhibition
Vanni, A.; Fiore, M.; De Salvia, R.; Cundari, E.; Ricordy, R.; Ceccarelli, R.; Degrassi, F.
Mutation Research 401(1-2): 55-63
1998
ISSN/ISBN: 0027-5107 PMID: 9639674 Document Number: 494371
beta-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, beta-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 beta-lapachone exerts its genotoxic action in cultured mammalian cells. Flow cytometry analysis of beta-lapachone-treated CHO cells indicated a selective cytotoxic effect upon S phase of the cell cycle. beta-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, beta-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 beta-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 beta-lapachone in CHO cells.