LINALOOL AS AN ANTICANCER-AGENT: MOLECULAR MECHANISMS OF ACTION AND ITS ENCAPSULATION IN NANODELIVERY SYSTEMS FOR CANCER THERAPY

CRESPO R; STÄRKEL P; DE BRAVO MG; CASTRO MA; CASTRO GR; RODENAK-KLADNIEW B; ISLAN GA; CRESPO R; DE BRAVO MG; STÄRKEL P; CASTRO MA; RODENAK-KLADNIEW B; CASTRO GR; ISLAN GA

Buenos Aires

Congreso; REUNION CONJUNTA DE SOCIEDADES DE BIOCIENCIAS 2017; 2017

Sociedad Argentina de Investigación Bioquímica y Biología Molecular (SAIB)

Linalool (LN) is a monoterpene found in essential oilsof many plants with multiple pharmacological effectsincluding anticancer activity. We have previously shown the ability of LN toimpair cancer cellsviability, however, to be considered as a potentialanticancer-drug, it is still necessary to elucidatethe specific mechanisms ofaction involved and improve its administration and bioavailability.For thispurpose we firstanalyzed the antiproliferative mechanisms of action of linaloolin HepG2 cells.Cells were treated with LN at different times and concentrationsand cell proliferation (BrdU incorporation), cell cycle progression (flowcytometry -FC-, western blot -WB-) mitochondrial membrane potential (MMP) andreactive oxygen species (ROS)(fluorescence microscopy -FM- and FC), and MAPKand Akt/mTOR activities (WB) were evaluated.LN inhibited CP by G0/G1 arrestthroughdownregulation of Cdk4, cyclin A and cyclin E and increasingp27 inhibitor, andat longer times, it also inducedapoptosis.LN stimulated ROS generation whichwere, at least in part, responsible for the cytotoxic effects since theantioxidant N-acetyl-L-cysteine (NAC) significantly prevented cell death. LN alsopromoted Akt inhibition, MAPKs activation(ERK, JNK and p38) and MMPdepolarization. NACprevented JNK activation and MMP depolarization, both ofthem associated with apoptosis, suggesting a direct role of ROS in LN-inducedapoptosis. Thereafter, we developed a novel delivery system based in LN-loadedsolid lipid nanoparticles(LN-SLN) of different composition, whose anticanceractivities and cellular uptake were assessed. Higher inhibitory effects werefound for LN-SLN in comparison with free LN (MTT assay). Additionally, thecellular uptake of SLN was proved by FM, enhancing the ability of SLN to deliverLN into the cells.Our results suggest that LNshould be considered as apotential anticancer agent and its loading into SLN would improve its bioavailabilityand efficiency.