Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), CONICET-UNLP, CCT-La Plata, Facultad de Ciencias Médicas, La Plata, Argentina.
Chem Biol Interact. 2014 May 5;214:57-68. doi: 10.1016/j.cbi.2014.02.013. Epub 2014 Mar 12.
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.
单萜是具有多种对甲羟戊酸途径（MP）作用的天然植物烃，而他汀类药物竞争性抑制羟甲基戊二酰基辅酶 A 还原酶（HMGCR），即 MP 的限速酶。单萜类化合物和他汀类药物已被证明能够抑制增殖和胆固醇生成。本研究评估了两种单萜：芳樟醇和 1,8-桉叶素——单独、相互组合或与辛伐他汀单独组合——对肝来源（HepG2）和肝外（A549）细胞系的体外增殖和抗胆固醇生成作用。这三种化合物单独以剂量依赖性方式抑制细胞增殖，而它们的两两组合在两种细胞系中产生协同的增殖抑制作用。用 [(14)C]乙酸进行的掺入实验表明，芳樟醇和 1,8-桉叶素抑制 MP，可能在不同部位，导致胆固醇生成减少和其他 MP 中间产物和产物积累。芳樟醇或 1,8-桉叶素，单独或与辛伐他汀一起，协同抑制胆固醇合成。在低浓度下，两种单萜均抑制胆固醇合成的特定步骤，而在较高浓度下，HMGCR 水平下调。添加外源性甲羟戊酸未能逆转芳樟醇和 1,8-桉叶素对增殖的抑制作用，这表明 HMGCR 抑制本身不是这些药物的增殖活性的原因。这项工作表明，单萜类化合物相互组合，或单独与辛伐他汀组合，协同抑制所研究的人细胞系的增殖和胆固醇生成，从而有助于更清楚地了解精油成分的作用，以及它们与他汀类药物在靶向复杂代谢途径中的特定靶点的结合。
