Docosahexaenoic acid metabolome in neural tumors: identification of cytotoxic intermediates

Abstract

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.

Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation

“…2 ), fi nding that LiCl prefeeding upregulated the brain concentration of 17-OH-DHA provides a new possible mechanism for lithium's reported neuroprotective action ( 57 ), in addition to downregulating the AA cascade ( 25,58 ). Supporting such a mechanism is epidemiological evidence that aspirin, which can increase identifi ed enzymes or pathways ( 16 ) are involved in 17-OH-DHA formation following lithium remains to be elucidated.…”

“…So far, only isolated soybean and potato 15-LOX and porcine 12-LOX have been shown to convert DHA to 17-OH-DHA in vitro ( 10,14,15 ). In addition, the oxygenation of DHA to 17-OH-DHA can be mediated by nonenzymatic autoxidation ( 16 ).…”

Length of concentrate finishing affects the fatty acid composition of grass-fed and genetically lean beef: an emphasis on trans-18:1 and conjugated linoleic acid profiles

“…The 10trans (t )-18:1 accumulates in intensively or concentrate-finished beef (Purchas et al, 2005;Leheska et al, 2008) and this has been associated with increased atherogenicity in animal models Roy et al, 2007). Forages are good sources of linolenic acid that leads to an enhanced n-3 polyunsaturated fatty acid (PUFA) content in beef products with a more desirable fatty acid composition for human health (Gleissman et al, 2010). Moreover, rumenic acid (RA, 9cis (c ), 11t-18:2) and its precursor vaccenic acid (VA, 11t-18:1) have been found to accumulate in forage-finished ruminants (Dugan et al, 2007;Kraft et al, 2008;Alfaia et al, 2009) and their consumption has been linked to a number of potential health benefits Field et al, 2009;Bassett et al, 2010).…”

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

“…More recent reports indicate that DHA also inhibits AA metabolism by CYP epoxygenases and hydroxylases [82]. In brain-metastatic melanoma and in a neuroblastoma cell line [116], DHA competition with AA resulted in decreased PGE 2 levels, with COX-2-mediated DHA metabolite PGE 3 significantly decreasing invasion in a dose-dependent manner [46]. DHA was also metabolized by recombinant COX-2 to 13-hydroxy DHA which has antiinflammatory properties and down-regulates cytokine production and neutrophil recruitment to sites of inflammation [117].…”