Omega-3 and omega-6 polyunsaturated fatty acids enhance arsenic trioxide efficacy in arsenic trioxide-resistant leukemic and solid tumor cells.

Recently we showed that the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) sensitizes arsenic trioxide (As 2 O 3 )-resistant tumor cells to a clinically achievable concentration (1 μM) of AS 2 O 3 via a reactive oxygen species (ROS)-dependent mechanism. The aim of the present study was to evaluate, whether this combined effect of As 2 O 3 and DHA is also applicable to other PUFAs [i.e., eicospentaenoic acid (EPA), arachidonic acid (AA), and gamma-linolenic acid (GLA)]. Fourteen tumor cell lines were incubated with As 2 O 3 (1 μM), PUFA (25-100 μM), or the combination thereof (±vitamin E). Cell viability (colorimetric), apoptosis (bivariate annexin V/propidium iodide staining, detection of hypodiploid DNA), and thiobarbituric acid reactive substances (TBARS) were evaluated. Twelve of 14 As 2 O 3 -resistant cell lines tested were resistant to PUFA monotherapy. However, combined treatment with As 2 O 3 and either PUFA significantly reduced cell viability in a dose-dependent manner with AA being the most potent As 2 O 3 enhancer. The combined cytotoxic effect of As 2O3 /AA treatment was due to induction of apoptosis, preceded by increased intracellular TBARS and was abolished by the antioxidant vitamin E. Importantly, the combined effect of As 2 O 3 and AA was selectively toxic for malignant cells because no cytotoxic effect was observed in normal skin fibroblasts and human microvascular endothelial cells. In conclusion, our study shows that also other PUFAs than DHA—and in particular the ω-6-PUFA AA—can be used as effective modulators of tumor cell chemosensitivity to clinically achievable concentrations of As 2 O 3 . Enhanced lipid peroxidation most likely constitutes the key mechanism for the combined effect.