Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets

• Published in: Biochimica et biophysica acta 2014-06, Vol.1838 (6), p.1628-1637
• Main Authors: Piotto, Stefano, Concilio, Simona, Bianchino, Erminia, Iannelli, Pio, López, David J., Terés, Silvia, Ibarguren, Maitane, Barceló-Coblijn, Gwendolyn, Martin, Maria Laura, Guardiola-Serrano, Francisca, Alonso-Sande, María, Funari, Sérgio S., Busquets, Xavier, Escribá, Pablo V.
• Format: Article
• Language: English
• Subjects: 2-Hydroxyoleic acid; Animals; Anti-cancer drug; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Proliferation - drug effects; Forkhead Transcription Factors - physiology; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Humans; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Membrane lipid therapy; Membrane Lipids - chemistry; Membrane Lipids - metabolism; Membrane physical state; Mice; Mice, Nude; Models, Chemical; Molecular dynamics; Molecular Dynamics Simulation; Oleic Acids - chemistry; Oleic Acids - pharmacology; Signal Transduction - drug effects; Stereoisomerism; Transferases (Other Substituted Phosphate Groups) - metabolism; Tumor Cells, Cultured; X-Ray Diffraction
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/j.bbamem.2013.12.023

The complex dual mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent anti-tumor compound used in membrane lipid therapy (MLT), has yet to be fully elucidated. It has been demonstrated that 2OHOA increases the sphingomyelin (SM) cell content via SM synthase (SGMS) activation. Its presence in membranes provokes changes in the membrane lipid structure that induce the translocation of PKC to the membrane and the subsequent overexpression of CDK inhibitor proteins (e.g., p21Cip1). In addition, 2OHOA also induces the translocation of Ras to the cytoplasm, provoking the silencing of MAPK and its related pathways. These two differential modes of action are triggered by the interactions of 2OHOA with either lipids or proteins. To investigate the molecular basis of the different interactions of 2OHOA with membrane lipids and proteins, we synthesized the R and S enantiomers of this compound. A molecular dynamics study indicated that both enantiomers interact similarly with lipid bilayers, which was further confirmed by X-ray diffraction studies. By contrast, only the S enantiomer was able to activate SMS in human glioma U118 cells. Moreover, the anti-tumor efficacy of the S enantiomer was greater than that of the R enantiomer, as the former can act through both MLT mechanisms. The present study provides additional information on this novel therapeutic approach and on the magnitude of the therapeutic effects of type-1 and type-2 MLT approaches. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy. [Display omitted] •The interaction of 2OHOA enantiomers with membranes, and that of other fatty acids, was studied using molecular modeling.•Each fatty acid had different regulatory effects on lipid structure but the behavior of both 2OHOA enantiomers was similar.•Only the S enantiomer of 2OHOA induced SMS activity, normalizing the PE:SM ratio in cancer cells.•In this context, the S 2OHOA enantiomer exerts a more potent anti-tumor effect than R enantiomer.•This work highlights the relevant structural features of drug–lipid and drug–protein interactions.