Correlation between inhibition of mevalonate pathway and hypolipidemic and antitumoral effect of isoprenoids

MARGARITA GARCÍA DE BRAVO; ROSANA CRESPO; MARIANELA GALLE; SANDRA MONTERO VILLEGAS; BORIS RODENAK KLADNIEW; MÓNICA POLO

Congreso; 54th International Conference on the Bioscience of Lipids: Linking Transcription to Physiology in Lipidomics; 2013

Correlation between inhibition of mevalonate pathway and hypolipidemic and antitumoral effect of isoprenoids Margarita García de Bravo, Rosana Crespo, Marianela Galle, Sandra Montero Villegas, Boris Rodenak Kladniev and Mónica Polo INIBIOLP (CCT-La Plata-CONICET-UNLP) Calles 60 y 120, La Plata-Argentina Isoprenoids are natural compounds present in the essential oils (EOs) of many aromatic plants. They have attracted interest for its potential antitumor and hypolipidemic properties. To evaluate those properties and the mechanisms of action of several monoterpenes (Mts) and C. reticulate and L. alba EOs, we performed in vitro and in vivo assays using lung epithelial (A549) and hepatoma (HepG2) human cell lines as well as A549 bearer nude mice. We determined viability and cell proliferation by trypan blue exclusion test and MTT assay, apoptosis by TUNEL assay and caspase- 3 activity and lipid synthesis by [14C]acetate incorporation. HMGCR, LDLR and SREBP-2 expression were analyzed by real-time RT-PCR. HMGCR and membrane-bound Ras protein levels were determined by Western blots and HMGCR activity by spectrophotometric assays. We demonstrated that all Mts tested decrease cholesterogenesis and proliferation and increase apoptosis but EOs have higher effects than pure compounds suggesting synergic effects. Cholesterogenesis and HMGCR levels decrease but the incorporation of [14C]acetate into other nonsaponifiable lipids increase indicating the existence of a second control point in the mevalonate pathway between squalene and cholesterol. Geraniol (G), used as Mts model, inhibits HMGCR at post-transcriptional level and increases liver LDLR expression which would cause hypocholesterolaemiant effect detected in mice. G also decreases membrane-bound Ras, which would indicate a decrease in the prenylation of this cell-cycle regulatory protein. The antiproliferative effect is not reversed by mevalonate addition whereby, further to HMGCR inhibition, other dose-dependent actions exist through which Mts can impact mevalonate pathway and consequently inhibit cell proliferation and induce apoptosis. Data here point to the role of EOs in regulating the complex pathway that could contribute to a more effective design of drugs for fighting cancer and/or cardiovascular diseases.