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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 18, 2005; DOI: 10.1124/jpet.105.088716

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Jordi Martinez
Antonio Gutierrez
Jesus Casas
Victoria Llado
Alicia Lopez-Bellan
Joan Besalduch
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Received for publication April 28, 2005.
Revised July 14, 2005.
Accepted for publication July 14, 2005.

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

Jordi Martinez 1, Antonio Gutierrez 2, Jesus Casas 1, Victoria Llado 1, Alicia Lopez-Bellan 1, Joan Besalduch 2, Ana Dopazo 3, Pablo V. Escriba 1*

1 University of the Balearic Islands 2 Son Dureta Hospital 3 National Center for Cardiovascular Research

* Address correspondence to: E-mail: pablo.escriba{at}uib.es

Abstract

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 PKC{alpha} 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{alpha} activation and p21CIP 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 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 appear to be involved in its pharmacological mechanism. Interestingly, while the changes induced by OA were only modest, they may reflect the beneficial effects of high olive oil intake against cancer.


Key words: Cell cycle, E2F-1, Lipid therapy, Minerval, hydroxyoleic acid, pRb


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[Abstract] [Full Text] [PDF]


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