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Research ArticleDrug Discovery and Translational Medicine

The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase Cα– and Extracellular Signal-Regulated Kinase 1/2–Dependent Mechanism

Francisca Guardiola-Serrano, Roberto Beteta-Göbel, Raquel Rodríguez-Lorca, Maitane Ibarguren, David J. López, Silvia Terés, Rafael Alvarez, María Alonso-Sande, Xavier Busquets and Pablo V. Escribá
Journal of Pharmacology and Experimental Therapeutics August 2015, 354 (2) 213-224; DOI: https://doi.org/10.1124/jpet.114.222281
Francisca Guardiola-Serrano
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Roberto Beteta-Göbel
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Raquel Rodríguez-Lorca
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Maitane Ibarguren
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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David J. López
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Silvia Terés
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Rafael Alvarez
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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María Alonso-Sande
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Xavier Busquets
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Pablo V. Escribá
Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (F.G.-S., R.B.-G., R.R.-L., M.I., D.J.L., S.T., R.A., M.A.-S., X.B., P.V.E.); and Lipopharma Therapeutics S.L., Palma de Mallorca, Spain (M.I., D.J.L., S.T., R.A., M.A.-S.).
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Abstract

Membrane lipid therapy is a novel approach to rationally design or discover therapeutic molecules that target membrane lipids. This strategy has been used to design synthetic fatty acid analogs that are currently under study in clinical trials for the treatment of cancer. In this context, and with the aim of controlling tumor cell growth, we have designed and synthesized a hydroxylated analog of triolein, hydroxytriolein (HTO). Both triolein and HTO regulate the biophysical properties of model membranes, and they inhibit the growth of non–small-cell lung cancer (NSCLC) cell lines in vitro. The molecular mechanism underlying the antiproliferative effect of HTO involves regulation of the lipid membrane structure, protein kinase C-α and extracellular signal-regulated kinase activation, the production of reactive oxygen species, and autophagy. In vivo studies on a mouse model of NSCLC showed that HTO, but not triolein, impairs tumor growth, which could be associated with the relative resistance of HTO to enzymatic degradation. The data presented explain in part why olive oil (whose main component is the triacylglycerol triolein) is preventive but not therapeutic, and they demonstrate a potent effect of HTO against cancer. HTO shows a good safety profile, it can be administered orally, and it does not induce nontumor cell (fibroblast) death in vitro or side effects in mice, reflecting its specificity for cancer cells. For these reasons, HTO is a good candidate as a drug to combat cancer that acts by regulating lipid structure and function in the cancer cell membrane.

Footnotes

    • Received December 22, 2014.
    • Accepted June 9, 2015.
  • This work was supported by the Ministerio de Economía y Competitividad [Grants BIO2010-21132 and BIO2013-49006-C2-1-R]; the Marathon Foundation; and the AECC from the Balearic Islands. F.G.-S. holds a contract from the “Fundación Científica de la Asociación Española Contra el Cáncer” which was paid in part by an “Acció especial” from the Government of the Balearic Islands. M.I. and D.J.L. were supported by Torres-Quevedo Research Contracts from the Spanish Ministerio de Economía y Competitividad [PTQ-10-04214 and PTQ-09-02-02113].

  • dx.doi.org/10.1124/jpet.114.222281.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 354 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 354, Issue 2
1 Aug 2015
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Research ArticleDrug Discovery and Translational Medicine

HTO Inhibits Lung Cancer Cell Proliferation.

Francisca Guardiola-Serrano, Roberto Beteta-Göbel, Raquel Rodríguez-Lorca, Maitane Ibarguren, David J. López, Silvia Terés, Rafael Alvarez, María Alonso-Sande, Xavier Busquets and Pablo V. Escribá
Journal of Pharmacology and Experimental Therapeutics August 1, 2015, 354 (2) 213-224; DOI: https://doi.org/10.1124/jpet.114.222281

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Research ArticleDrug Discovery and Translational Medicine

HTO Inhibits Lung Cancer Cell Proliferation.

Francisca Guardiola-Serrano, Roberto Beteta-Göbel, Raquel Rodríguez-Lorca, Maitane Ibarguren, David J. López, Silvia Terés, Rafael Alvarez, María Alonso-Sande, Xavier Busquets and Pablo V. Escribá
Journal of Pharmacology and Experimental Therapeutics August 1, 2015, 354 (2) 213-224; DOI: https://doi.org/10.1124/jpet.114.222281
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