title: The repression of E2F-1 is critical for the activity of Minerval against cancer.
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) 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 PKCalpha 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.
authors: 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.
authors: Jordi
authors: J
authors: Martínez
authors: Antonio
authors: A
authors: Gutiérrez
authors: Jesús
authors: J
authors: Casas
authors: Victoria
authors: V
authors: Lladó
authors: Alicia
authors: A
authors: López-Bellan
authors: Joan
authors: J
authors: Besalduch
authors: Ana
authors: A
authors: Dopazo
authors: Pablo V
authors: PV
authors: Escribá
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D016213:Cyclins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019301:Oleic Acid / Q000494:pharmacology; D009829:Oleic Acids / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: C497101:2-hydroxy-9-cis-octadecenoic acid; D000970:Antineoplastic Agents; D016213:Cyclins; D009829:Oleic Acids; D016160:Retinoblastoma Protein; D019301:Oleic Acid; D011493:Protein Kinase C