Lipids as clinical drugs, lipids as drug targets

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Abstracts / Chemistry and Physics of Lipids 163S (2010) S1–S18

effect does not depend on increased Taxol expulsion from cells, or decreased entry of cells into G2/M. Rather, LPA enables breast cancer cells that are pretreated with Taxol in delipidated serum to normalize mitotic spindle formation and divide. This LPA effect depends on phosphatidylinositol 3-kinase activity and a decrease in the Taxol-induced production of the pro-apoptotic lipid, ceramide. LPA also increases the expressions of anti-apoptotic proteins and those that modulate spindle formation and microtubule dynamicity. We conclude that these signaling effects could also contribute to resistance to the actions of other chemotherapeutic agents. doi:10.1016/j.chemphyslip.2010.05.025 SO10 Lipids as clinical drugs, lipids as drug targets Pablo V. Escribá ∗ , Xavier Busquets, Silvia Terés, Victoria Lladó, Gwendolyn Barceó-Coblijn, Daniel H. Lopez, David López Laboratory of Molecular and Cellular Biomedicine, Department of Biology-IUNICS, University of the Balearic Islands, Spain Background: In several human pathologies it has been shown that the type and abundance of membrane lipids are altered. Moreover, most signaling pathways associated with the etiology of human diseases are regulated by membrane proteins. Hypothesis: Membrane lipids and the structures they form control the localization and activity of relevant signaling membrane proteins, making it possible the design of lipid-interacting molecules to regulate the propagation of the messages. This work was designed to evaluate the therapeutic potential of synthetic lipids that interact with membranes in the treatment of various human pathologies. Results: A series of 2-hydroxy derivatives of MUFAs and PUFAs was tested in cellular and animal models of human pathologies. In this context, 2-hydroxyoleic acid (2OHOA) showed to be more potent and less toxic than the drugs of reference in the treatment of lung cancer and glioma. In addition, this compound also reduced blood pressure in hypertensive rats to normal levels, and body weight. In rats with spinal cord injury, the complex albumin–2OHOA induced recoveries in the mobility of rats of up to 80%, whereas untreated rats only recovered ca. 5% of the motor mobility. The arachidonic acid derivative, 2hydroxy-arachidonic acid, showed a greater anti-inflammatory activity in mice than those of ibuprofen and cortisone. Finally, 2hydroxy-docosahexaenoic (2OHDHA) acid treatments prevented the development of Alzheimer’s disease in 5XFAD mice. Conclusions: The high efficacy, lack of toxicity and oral administration of the above-mentioned synthetic lipids indicates that therapies targeted at membrane lipids can be useful in the treatment of human pathologies. doi:10.1016/j.chemphyslip.2010.05.026

SO11 A ceramide analog directly inhibits cPLA2 activity and consequent PGE2 formation in LPS-stimulated macrophages Meir Goldsmith 1 , Ala Daka 1 , Nadia F. Lamour 2,3,4 , Roi Mashiach 5 , Michael M. Meijler 5 , Charles E. Chalfant 2,3,4 , Tsaffrir Zor 1,∗ 1

Department of Biochemistry and Molecular Biology, Life Sciences Institute, Tel-Aviv University, Tel-Aviv 69978, Israel 2 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University-School of Medicine, Richmond, VA 23298-0614, United States 3 Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249, United States 4 The Massey Cancer Center, Richmond, VA 23298, United States 5 Department of Chemistry, Ben-Gurion University of the Negev, Be’erSheva 84105, Israel

Prostaglandin E2 (PGE2 ) is an important mediator of the inflammatory response. The sphingolipid ceramide-1-phosphate (C1P) stimulates PGE2 production via its positive regulation of cytosolic phospholipase A2 (cPLA2 ) activity. Phospho-ceramide analogue-1 (PCERA-1) was previously reported to modulate pro- and antiinflammatory cytokine production. We hypothesized that PCERA-1 would also regulate cPLA2 activity and PGE2 production. We show here that PCERA-1 inhibited lipopolysaccharide (LPS)-stimulated PGE2 production in RAW264.7 macrophages, without affecting cyclooxygenase-2 (COX-2) expression. PCERA-1 efficiently suppressed arachidonic acid (AA) release in response to LPS, but not in response to zymosan. Moreover, PCERA-1 was ineffective when AA formation was induced by a co-stimulus of LPS and zymosan, indicating that the mechanism of PLA2 activation by zymosan is dominant over its mechanism of activation by LPS. The dephosphorylated derivative of PCERA-1, ceramide analogue-1 (CERA-1), mimicked the inhibitory effect of PCERA-1 on AA release and PGE2 production in macrophages. Importantly, PCERA-1 and C1P stimulated the enzymatic activity of cPLA2 in an in vitro assay, whereas CERA-1 and ceramide inhibited both basal and C1P-stimulated cPLA2 activity. Collectively, these results indicate that CERA-1 suppresses AA release and subsequent PGE2 production in LPSstimulated macrophages by direct interaction with cPLA2 , and suggest that ceramide may similarly counteract C1P effect on cPLA2 activity in cells. The suppression of PGE2 production is suggested to contribute to the anti-inflammatory action of PCERA-1. doi:10.1016/j.chemphyslip.2010.05.027 SO12 Overview lipidomics of Schnyder crystalline corneal dystrophy: global effects of UbiA prenyltransferase domain containing 1 deficiency on lipid metabolism Hiromasa Tojo 1,∗ , Yoko Akune 2 , Hiroshi Mochizuki 2 , Masakazu Yamada 2 1

Department of Biophysics and Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan 2 Division for Vision Research, National Institute of Sensory Organs, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive bilateral corneal opacification due to an increased deposition of lipids including cholesterol and sphingomyelin in the central cornea. Its causal gene has been identified as the UBIAD1 gene that encodes the UbiA prenyltransferase domain containing 1 protein. To address the