A naphthoquinone compound (12,13-dihydro-N-methyl-6,11,13-troxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalene-5,12-imine) known as TU100 was previously synthesized as a potential chemotherapeutic agent. Evaluation of its biological activity using cancer cell lines revealed that TU100 is cytotoxic in part because it generates reactive oxygen species that likely cause DNA damage, cell cycle arrest, and ultimately apoptosis. Based on these results we hypothesized that ascorbic acid might promote TU100 production of reactive oxygen species via a redox cycling mechanism. To test this idea cancer cell lines were treated with varying concentrations of TU100 in the presence and absence of ascorbic acid, followed by evaluation of cell viability using a resazurin-based fluorescent assay. Our results show that ascorbic acid greatly enhanced the cytotoxicity of TU100, such that the cancer cells died at much lower concentrations of the drug. To determine if this enhanced cell death was due to increased production of reactive oxygen species, we utilized dihydroethidium bromide to measure their production in cells treated with TU100 with and without ascorbic acid. Both fluorescence microscopy and quantitative measurement of fluorescence using a plate reader revealed that ascorbic acid greatly increases the production of reactive oxygen species produced in the presence of TU100. These results provide further evidence that TU100 cytotoxicity is mediated by production of reactive oxygen species, and raise the possibility of using ascorbic acid to enhance this effect in order to promote cancer cell death.

Ascorbic acid enhances cytotoxicity of a novel naphthoquinone containing a modified anthracycline Ring System

249th National Meeting (2015)

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