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

P STARKEL; R CRESPO; G ISLÁN; GR CASTRO; B RODENAK KLADNIEW; MA CASTRO; M GARCÍA DE BRAVO

Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

Linalool (LN) is a monoterpene found in essential oils of manyplants with multiple pharmacological effects including anticanceractivity. We have previously shown the ability of LN to impair cancercells viability, however, to be considered as a potential anticancer-drug, it is still necessary to elucidate the specific mechanismsof action involved and improve its administration and bioavailability.For this purpose we first analyzed the antiproliferative mechanismsof action of linalool in HepG2 cells. Cells were treated with LN atdifferent times and concentrations and cell proliferation (BrdU incorporation),cell cycle progression (flow cytometry -FC-, westernblot -WB-) mitochondrial membrane potential (MMP) and reactiveoxygen species (ROS) (fluorescence microscopy -FM- and FC), andMAPK and Akt/mTOR activities (WB) were evaluated. LN inhibitedCP by G0/G1 arrest through downregulation of Cdk4, cyclin A andcyclin E and increasing p27 inhibitor, and at longer times, it alsoinduced apoptosis. LN stimulated ROS generation which were, atleast in part, responsible for the cytotoxic effects since the antioxidantN-acetyl-L-cysteine (NAC) significantly prevented cell death.LN also promoted Akt inhibition, MAPKs activation (ERK, JNK andp38) and MMP depolarization. NAC prevented JNK activation andMMP depolarization, both of them associated with apoptosis, suggestinga direct role of ROS in LN-induced apoptosis. Thereafter, wedeveloped a novel delivery system based in LN-loaded solid lipid nanoparticles(LN-SLN) of different composition, whose anticancer activitiesand cellular uptake were assessed. Higher inhibitory effectswere found for LN-SLN in comparison with free LN (MTT assay). Additionally,the cellular uptake of SLN was proved by FM, enhancingthe ability of SLN to deliver LN into the cells. Our results suggestthat LN should be considered as a potential anticancer agent andits loading into SLN would improve its bioavailability and efficiency.