Mónica Patricia Polo

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

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.

Age changes in the activity of liver 3-hydroxy-3-methylglutaryl–CoA reductase in female rats: influence of mammary pathology

Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase is a highly regulated enzyme which shows a marked circadian rhythmicity. We studied the impact of aging on this rhythm as well as the degree of correlation between age changes in circulating pituitary hormone levels and liver reductase activity in young (4 months) and old (33 months) Sprague-Dawley female rats. Lipid composition was also assessed in plasma and liver microsomes. The maximal activity (midnight) of HMG-CoA reductase fell from 864 +/- 28 pmol mevalonate/min/mg protein in the young rats to 552 +/- 45 pmol/min/mg protein in the old animals, whereas significant change was not observed in the basal (noon) activity levels of the enzyme. Noon serum cholesterol, but not midnight values, was significantly higher in the old rats. Liver cholesterol levels were similar in young and old rats. In old rats, fatty acid composition of liver microsomes revealed an increase in linoleic acid concurrently with a significant decrease in arachidonic acid (AA). A significant correlation was not detected between the age changes in pituitary hormone (GH, PRL, TSH, FSH) serum levels and those in reductase activity. On the other hand, a significant positive correlation was found in the old rats between hepatic reductase activity and the severity of mammary pathology. We conclude that, like most biological rhythms, HMG-CoA reductase circadian fluctuation decreases in amplitude with age. This change does not seem to be linked to the alterations of neuroendocrine function associated with the aging process. The presence of growing mammary tumors seems to stimulate liver reductase activity, which may constitute an adaptive response of the enzyme to cholesterol demand by the growing neoplastic tissue.

Partial prevention of hepatic lipid alterations in nude mice by neonatal thymulin gene therapy.

During adult life athymic (nude) male mice display not only a severe T-cell-related immunodeficiency but also endocrine imbalances and a moderate hyperglycemia. We studied the impact of congential athymia on hepatic lipid composition and also assessed the ability of neonatal thymulin gene therapy to prevent the effects of athymia. We constructed a recombinant adenoviral vector, RAd-metFTS, expression a synthetic DNA sequence encoding met-FTS, an analog of the thymic peptide facteur thymique sérique (FTS), whose Zn-bound biologically active form is known as thymulin. On postnatal day 1–2 homozygous (nu/nu) nude and heterozygous (nu/+) mice were injected with 108 pfu of RAd-metFTS or RAd-βgal (control vector) intramuscularly. The animals were processed at 52 d of age. Serum thymulin, glycemia, hepatic phospholipid FA compostion and free and esterified cholesterol were determined. Adult homozygous male nudes were significantly (P<0.01) hyperglycemic when compared with their heterozygous counterparts (2.04 vs. 1.40 g/L, respectively). The relative percentage of 16∶0, 18∶1n−9, and 18∶1n−7 FA was lower, whereas that of 18∶0, 20∶4n−6, and 22∶6n−3 FA was higher, in hepatic phospholipid (PL) of nu/nu animals as compared with their nu/+ counterparts. Some of these alterations, such as that in the relative content of 22∶6n−3 in liver PL and the unsaturation index, were completely or partially prevented by neonatal thymulin gene therapy. We conclude that the thymus influences lipid metabolism and that thymulin is involved in this modulatory activity.