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 protein kinase C (PKC) α 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 PKCα 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 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.
Footnotes
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This work was supported by Grants SAF2001-0839, SAF2003-00232, and SAF2004-05249 (Ministerio de Educación y Ciencia). “Fundacion Marathon”, “Conselleria de Sanitat”, and “Conselleria d'Economia, Hisenda i Innovació (Grants PRDIB-2002GC2-11 and PRID2004-10131) del Govern Balear” and “Centre Coordinador de Drogodependències” also provided funds for this work. J.C. was supported by a fellowship from the Spanish Ministerio de Educación y Ciencia. J.M. received the “Elsevier Young Scientist Award” for communication in the 2004 International Society for the Study of Fatty Acids and Lipids Meeting (Brighton, UK), showing some of the results included here.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.088716.
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ABBREVIATIONS: OA, oleic acid; PKC, protein kinase C; pRb, retinoblastoma protein; cdk, cyclin-dependent kinase; PBS, phosphate-buffered saline; PARP, poly ADP-ribose polymerase; RT-PCR, reverse transcription-polymerase chain reaction; RT, reverse transcription; PCR, polymerase chain reaction; CP, crossing point.
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↵1 These authors contributed equally to this work.
- Received April 28, 2005.
- Accepted July 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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