Eucalyptol and linalool: mechanisms underlying their antiproliferative effects on human tumor cells

RODENAK KLADNIEW BE; MONTERO VILLEGAS SM; POLO MP; GARCÍA DE BRAVO MM

Rosario

Congreso; L Reunión Anual de SAIB; 2014

Resumen Eucalyptol (Eu) and linalool (Ln) are natural isoprenoids with multiple effects on the mevalonate pathway (MP), a branched pathway essential for cholesterol synthesis and cell proliferation. In previous studies we demonstrated that Eu and Ln were capable of inhibiting cell proliferation in human liver (HepG2) and lung (A549) carcinoma cells. We herein studied the mechanisms involved in those inhibitory effects. Eu and Ln impaired HMG-CoA reductase (HMGCR, the rate-limiting enzyme in the MP) levels , however, the addition of exogenous mevalonate (the HMGCR product) was unable to restore cell growth. Cell cycle analysis showed a G0/G1 arrest produced by Eu and Ln in HepG2 and A549 cells. IC50 of Ln induced apoptosis in HepG2 cells as determined by caspase-3 activity and TUNEL assays, whereas at higher concentrations Eu and Ln triggered apoptosis in both cell types. Ras translocation to the membrane was inhibited by Ln without altering total Ras levels. Our results suggest that in our conditions Eu and Ln at their IC50 exert antitumor activity by inhibition of cell cycle progression in both cell types, meanwhile Ln is also able to induce apoptosis in HepG2 cells. HMGCR inhibition alone is not responsible for the antiproliferative activity of Eu and Ln. The inhibition of Ras translocation to the membrane could be one of the reasons for cell cycle arrest and apoptosis induction.