Beta-lapachone greatly enhances MMS lethality to human fibroblasts

beta-Lapachone is a naturally occurring tricyclic O-naphthoquinone. At microM concentrations it did not substantially affect viability, growth or DNA synthesis of cultured undamaged human fibroblasts. Cells exposed to minimally toxic concentrations of methyl methane sulfonate were strongly inhibited in these properties by beta-lapachone. The effects were not reversed by further incubation in the absence of beta-lapachone and were equal for initially quiescent or growing cells. Thus inhibitions were specific for damaged cells and did not involve replicative DNA synthesis. Inhibition of DNA strand break repair was demonstrated by alkaline elution, but unscheduled DNA synthesis was not inhibited. We propose that beta-lapachone inhibits a ligation step of DNA repair, in a manner perhaps similar to that reported for carbamoylating nitrosoureas. Other repair inhibitors differ significantly from beta-lapachone in their modes of action.