QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.088716v1 315/1/466    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Martínez, J. Articles by Escribá, P. V. Search for Related Content PubMed PubMed Citation Articles by Martínez, J. Articles by Escribá, P. V.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

The Repression of E2F-1 Is Critical for the Activity of Minerval against Cancer

Laboratory of Molecular and Cellular Biomedicine, Institut Universitari d'Investigacions en Ciències de la Salut, Associate Unit of the Consejo Superior de Investigaciones Cientificas, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain (J.M., J.C., V.L., A.L.-B., P.V.E.); Department of Hematology, Hospital Son Dureta, Palma de Mallorca, Spain (A.G., J.B.); and Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (A.D.)

The recently discovered anticancer drug Minerval (2-hydroxy-9-cis-octadecenoic acid) is a synthetic fatty acid that modifies the structure of the membrane. This restructuring facilitates the recruitment of protein kinase C (PKC) to membranes and is associated with the antineoplastic activity of Minerval in cellular and animal models of cancer. Minerval is a derivative of oleic acid (OA) with an enhanced antiproliferative activity in human cancer cells and animal models of cancer, which is associated with PKC activation and p21^CIP overexpression. However, the signaling cascades involved in its pharmacological activity remain largely unknown. Here, we showed that this drug induced cell cycle arrest before entry into S phase, human lung adenocarcinoma (A549) cells accumulating in the G₀/G₁ phase. This cell cycle arrest was associated with a marked decrease in the expression of E2F-1. This transcription factor activates several cell cycle-related genes, and, accordingly, the expression of certain cyclins and cyclin-dependent kinases (cdks) was markedly lower upon exposure to Minerval. The reduced availability of these kinase heterodimers was associated with reduced phosphorylation of the retinoblastoma protein (pRb) observed after drug treatment. Significantly, hypophosphorylated pRb remains bound to E2F-1 and maintains this transcription factor inactive. The modulation of these antiproliferative mechanisms by Minerval explains its anticancer potency, through a new therapeutic strategy that can be used to develop new antitumor drugs. On the other hand, apoptosis did not seem to be involved in its pharmacological mechanism. Interestingly, whereas the changes induced by OA were only modest, they may reflect the beneficial effects of high olive oil intake against cancer.

Address correspondence to: Dr. Pablo V. Escribá, Laboratory of Molecular and Cellular Biomedicine, Associate Unit of the "Instituto de la Grasa" (CSIC), IUNICS, Department of Biology, University of the Balearic Islands, Ctra. de Valldemossa Km 7.5, E-07122 Palma de Mallorca, Spain. E-mail: pablo.escriba{at}uib.es

This article has been cited by other articles:

				R. Alemany, O. Vogler, S. Teres, C. Egea, C. Baamonde, F. Barcelo, C. Delgado, K. H. Jakobs, and P. V. Escriba Antihypertensive action of 2-hydroxyoleic acid in SHRs via modulation of the protein kinase A pathway and Rho kinase J. Lipid Res., August 1, 2006; 47(8): 1762 - 1770. [Abstract] [Full Text] [PDF]