Mechanism of action of linalool involved in its antiproliferative effects on hepatocellular carcinoma cells

BORIS RODENAK KLADNIEW; MARIANELA GALLE; AGUSTINA CASTRO; SANDRA MONTERO VILLEGAS; ROSANA CRESPO; MÓNICA POLO; DE SAEGER C; STÄRKEL P; MARGARITA GARCÍA DE BRAVO

Puerto Varas

Congreso; 14th International Congress of Ethnopharmacology; 2014

Monoterpenes, like linalool (LN), are naturally occurring isoprenoids of ten carbons found in essential oils of many plants. It has been demonstrated that some isoprenoids have antiproliferative activities, phenomenon attributed to their multiple pharmacological effects on the mevalonate pathway (MP): the inhibition of the HMG-CoA reductase activity (HMGCR, the rate limiting step enzyme in the MP) and/or the inhibition of protein isoprenylation. Among these prenylated proteins, Ras family showed to be critical in human oncogenesis. They act as molecular switches controlling cell proliferation, apoptosis and survival. Prenylation of Ras enables it to associate with plasma membrane, which is required for its oncogenic activity. The aim of this work was to elucidate the potential mechanisms involved in the antiproliferative effects excerted by LN on human hepatoblastoma (HepG2) cells. For this purpose, cells were treatred with LN at different times and/or concentrations and cell proliferation (MTT, cell counting and BrdU incorporation), apoptosis (TUNEL), cell cycle analysis (flow cytometry), HMGCR levels and Ras subcellular localization were studied. Our results showed that LN inhibited HepG2 cell proliferation, arrested cell cycle progression in G0/G1 phase, induced apoptosis and diminished Ras levels in the membrane fraction. Moreover, HMGCR levels became down-regulated. Added exogenous mevalonate failed to reverse the inhibition of proliferation exerted by LN, suggesting that HMGCR inhibition alone is not responsible for the antiproliferative activity of this compound. This work contributes to a clearer understanding of the mechanisms of action of LN suggesting that its use could provide significant health benefits as a chemopreventive and/or chemotherapeutic agent.