title: Synergistic antiproliferative and anticholesterogenic effects of linalool, 1,8-cineole, and simvastatin on human cell lines.
abstract: Monoterpenes are naturally occurring plant hydrocarbons with multiple effects on the mevalonate pathway (MP), while statins competitively inhibit hydroxymethylglutarylcoenzyme-A reductase (HMGCR), the rate-limiting enzyme in the MP. Monoterpenes and statins proved capable of inhibiting both proliferation and cholesterogenesis. In the present study we assess the in vitro antiproliferative and anticholesterogenic effects of two monoterpenes: linalool and 1,8-cineole-either alone, in combination with each other, or combined individually with simvastatin-on liver-derived (HepG2) and extrahepatic (A549) cell lines. The three compounds alone inhibited cell proliferation in a dose-dependent fashion, while their pairwise combination produced synergistic antiproliferative effects in both cell lines. Incorporation experiments with [(14)C]acetate revealed that linalool and 1,8-cineole inhibited the MP, probably at different points, resulting in a reduction in cholesterogenesis and an accumulation of other MP intermediates and products. Linalool or 1,8-cineole, either together or individually with simvastatin, synergistically inhibited cholesterol synthesis. At low concentrations both monoterpenes inhibited steps specifically involved in cholesterol synthesis, whereas at higher concentrations HMGCR levels became down-regulated. Added exogenous mevalonate failed to reverse the inhibition of proliferation exerted by linalool and 1,8-cineole, suggesting that HMGCR inhibition alone is not responsible for the antiproliferative activity of those agents. This work demonstrates that monoterpenes in combination with each other, or individually in combination with simvastatin synergistically inhibits proliferation and cholesterogenesis in the human cell lines investigated, thus contributing to a clearer understanding of the action of essential-oil components, and their combination with the statins, in the targeting of specific points within a complex metabolic pathway.
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina. Electronic address: brodenak@med.unlp.edu.ar.
authors.forename: Boris
authors.initials: B
authors.lastname: Rodenak Kladniew
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
authors.forename: Mónica
authors.initials: M
authors.lastname: Polo
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
authors.forename: Sandra
authors.initials: S
authors.lastname: Montero Villegas
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
authors.forename: Marianela
authors.initials: M
authors.lastname: Galle
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
authors.forename: Rosana
authors.initials: R
authors.lastname: Crespo
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
authors.forename: Margarita
authors.initials: M
authors.lastname: García de Bravo
mesh_terms: D000080462:Acyclic Monoterpenes; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000096:biosynthesis*; D003511:Cyclohexanols / Q000494:pharmacology*; D004357:Drug Synergism; D004951:Esterification; D000077591:Eucalyptol; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D000080462:Acyclic Monoterpenes; D003511:Cyclohexanols; D039821:Monoterpenes; D002784:Cholesterol; D019821:Simvastatin; C018584:linalool; D000077591:Eucalyptol
keywords: 1,8-Cineole; Cholesterogenesis; Linalool; Proliferation; Simvastatin; Synergistic effects