Suppression by Geraniol of the Growth of A549 Human Lung Adenocarcinoma Cells and Inhibition of the Mevalonate Pathway in Culture and In Vivo: Potential Use in Cancer Chemotherapy

摘要

Geraniol (G)-a natural compound present in the essential oils of many aromatic plants-has attracted interest for its potential antitumor effects. The molecular mechanisms of the growth inhibition and apoptosis induced by G in cancer cells, however, remain unclear. In this study, we investigated the effects of G on cell proliferation in culture in A549 cells and in vivo in those same tumor cells implanted in nude mice fed diets supplemented with 25, 50, and 75 mmol G/kg. We demonstrated that G caused a dose-and time-dependent growth inhibition of A549 cells and tumor growth in vivo along with an induction of apoptosis. Moreover, further in vivo assays indicated that G decreased the levels of 3-hydroxymethylglutarylcoenzyme-A reductase-the rate-limiting enzyme in cholesterogenesis-in a dose-dependent manner along with cholesterogenesis and cholesterolemia in addition to reducing the amount of membrane-bound Ras protein. These results showed that the doses of G used in this work, though nontoxic to animals, clearly inhibited the mevalonate pathway, which is closely linked to cell proliferation and increased apoptosis in A549 tumors, but not in normal mouse-liver cells. Accordingly, we suggest that G displays significant antitumor activity and should be a promising candidate for cancer chemotherapy.