Recent reports indicate a broad spectrum of antileukemic activity for
arsenic trioxide (
As(2)O(3)) due to its ability to induce apoptosis via intracellular production of
reactive oxygen species (ROS). Despite its potent apoptotic mechanism,
As(2)O(3) is not equally effective in all leukemic cells, which has prompted a search for agents enhancing
As(2)O(3) 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 As(2)O(3)-mediated apoptosis in As(2)O(3)-resistant HL-60 cells. While 1 microM
As(2)O(3) or 25 microM DHA reduced cell viability to 85.8% +/- 2.9% and 69.2% +/- 3.6%, combined treatment with
As(2)O(3) 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
As(2)O(3) 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
As(2)O(3) and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of
As(2)O(3) and suggest that the combination of
As(2)O(3) and DHA could be more broadly applied in
leukemia therapy.