Docosahexaenoic acid enhances arsenic trioxide–mediated apoptosis in arsenic trioxide–resistant HL-60 cells

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Abstract
Recent reports indicate a broad spectrum of antileukemic activity for arsenic trioxide (As2O3) due to its ability to induce apoptosis via intracellular production of reactive oxygen species (ROS). Despite its potent apoptotic mechanism, As2O3 is not equally effective in all leukemic cells, which has prompted a search for agents enhancing As2O3 efficacy. Recently, evidence has been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may sensitize tumor cells to ROS-inducing anticancer agents. The aim of our investigation was to evaluate whether DHA enhances As2O3-mediated apoptosis in As2O3-resistant HL-60 cells. While 1 μM As2O3 or 25 μM DHA reduced cell viability to 85.8% ± 2.9% and 69.2% ± 3.6%, combined treatment with As2O3 and DHA reduced viability to 13.0% ± 9.9% with a concomitant increase of apoptosis. Apoptotic cell death was preceded by collapse of the mitochondrial membrane potential, increased expression of proapoptotic B-cell lymphoma protein-2–associated X protein (Bax), and caspase-3 activation. Importantly, the combined effect of As2O3 and DHA was associated with increased production of intracellular ROS and toxic lipid peroxidation products and was abolished by the antioxidant vitamin E or when oleic acid (a nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and toxic lipid peroxidation products most likely constitute the key mediators contributing to the combined effect of As2O3 and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of As2O3 and suggest that the combination of As2O3 and DHA could be more broadly applied in leukemia therapy.

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