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ORIGINAL ARTICLE

Membrane Structure Modulation, Protein Kinase C Activation, and Anticancer Activity of Minerval

Laboratory of Molecular and Cellular Biomedicine, Associate Unit of the Instituto de la Grasa (Consejo Superior de Investigaciones Cientificas), Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, Palma de Mallorca, Spain (J.M., O.V., J.C., F.B., R.A., J.P., T.N., C.B., S.T., C.S., P.V.E.); and Biomeasure Inc., Milford, Massachusetts (P.G.K.)

Abstract

Most drugs currently used for human therapy interact with proteins, altering their activity to modulate the pathological cell physiology. In contrast, 2-hydroxy-9-cis-octadecenoic acid (Minerval) was designed to modify the lipid organization of the membrane. Its structure was deduced following the guidelines of the mechanism of action previously proposed by us for certain antitumor drugs. The antiproliferative activity of Minerval supports the above-mentioned hypothesis. This molecule augments the propensity of membrane lipids to organize into nonlamellar (hexagonal H_II) phases, promoting the subsequent recruitment of protein kinase C (PKC) to the cell membrane. The binding of the enzyme to membranes was marked and significantly elevated by Minerval in model (liposomes) and cell (A549) membranes and in heart membranes from animals treated with this drug. In addition, Minerval induced increased PKC expression (mRNA and protein levels) in A549 cells. This drug also induced PKC activation, which led to a p53-independent increase in p21^CIP expression, followed by a decrease in the cellular concentrations of cyclins A, B, and D3 and cdk2. These molecular changes impaired the cell cycle progression of A549 cells. At the cellular and physiological level, administration of Minerval inhibited the growth of cancer cells and exerted antitumor effects in animal models of cancer without apparent histological toxicity. The present results support the potential use of Minerval and related compounds in the treatment of tumor pathologies.

Address correspondence to: Dr. Pablo V. Escribá, Laboratory of Molecular and Cellular Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, Ctra. de Valldemossa km 7,5, E-07122 Palma de Mallorca, Spain. E-mail: pablo.escriba{at}uib.es

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