Differential augmentative effects of buthionine sulfoximine and ascorbic acid in As₂O₃-induced ovarian cancer cell death: Oxidative stress-independent and -dependent cytotoxic potentiation

The potential of arsenic trioxide (As₂O₃) as a novel therapy against ovarian cancer has been progressively recognized. Its prospective usefulness for treatment of this malignancy either alone or in combination with other chemotherapeutic agents has been increasingly explored. In this study, we attempted to enhance the cytotoxicity of As₂O ₃ in ovarian cancer cells through manipulation of cellular glutathione (GSH) levels using either buthionine sulfoximine (BSO) or ascorbic acid (AA). Results from our studies showed that combinatorial therapies using As₂O₃ with either low dose BSO or only pharmacological doses of AA acted synergistically to enhance the cytotoxicity of As ₂O₃ in ovarian tumor cells. With these regimens, therapeutic selectivity was observed with preferential killing of ovarian tumor cells over normal fibroblast controls. Furthermore, contrary to previous reports, enhancement of As₂O₃-mediated cell killing by these two agents was propagated through different effects. With BSO, apoptotic and non-apoptotic cell death enhancement were mediated through increased arsenic accumulation and GSH depletion that occurred independently of reactive oxygen species. With pharmacological doses of AA, increase in cell death proceeded through non-apoptotic routes via an oxidative stress-related pathway independent of GSH levels. Taken together, these results indicate that GSH depleting agents or pro-oxidative chemicals have capabilities of improving the utility of As₂O₃ in ovarian cancer management.