Docosahexaenoic acid (DHA) protects neural cells from stress-induced apoptosis. On the contrary, DHA exerts anticancer effects, and we have shown that DHA induces apoptosis in
neuroblastoma, an embryonal
tumor of the sympathetic nervous system. We now investigate the DHA metabolome in
neuroblastoma using a targeted lipidomic approach in order to elucidate the mechanisms behind the DHA-induced cytotoxicity. LC-MS/MS analysis was used to identify DHA-derived
lipid mediators in
neuroblastoma cells. Presence of the
15-lipoxygenase enzyme was investigated using immunoblotting, and cytotoxic potency of DHA and DHA-derived compounds was compared using the MTT cell viability assay.
Neuroblastoma cells metabolized DHA to
17-hydroxydocosahexaenoic acid (17-HDHA) via 17-hydroperoxydocosahexaenoic
acid (17-HpDHA) through
15-lipoxygenase and autoxidation. In contrast to normal neural cells,
neuroblastoma cells did not produce the anti-inflammatory and protective
lipid mediators, resolvins and protectins.
17-HpDHA had significant cytotoxic potency, with an IC(50) of 3-6 microM at 72 h, compared to 12-15 microM for DHA.
alpha-Tocopherol protected cells from 17-HpDHA-induced cytotoxicity. DHA inhibited secretion of prostaglandin-E(2) and augmented the cytotoxic potency of the cyclooxygenase-2-inhibitor
celecoxib. The cytotoxic effect of DHA in
neuroblastoma is mediated through production of hydroperoxy
fatty acids that accumulate to toxic intracellular levels with restricted production of its products, resolvins and protectins.-Gleissman, H., Yang, R., Martinod, K., Lindskog, M., Serhan, C. N., Johnsen, J. I., Kogner, P.
Docosahexaenoic acid metabolome in neural
tumors: identification of cytotoxic intermediates.