INIBIOLP   05426
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE LA PLATA "PROF. DR. RODOLFO R. BRENNER"
Unidad Ejecutora - UE
artículos
Título:
1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs
Autor/es:
RODENAK KLADNIEW B; GALLE M; CASTRO A; CRESPO R; STÄRKEL, PETER; RODENAK KLADNIEW B; GALLE M; CASTRO A; CRESPO R; STÄRKEL, PETER
Revista:
LIFE SCIENCES
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2020 vol. 243
ISSN:
0024-3205
Resumen:
Aims: 1,8-Cineole is a plant-derived monoterpene and a major constituent of Eucalyptus essential oil. Previously,we demonstrated that 1,8-cineole inhibited hepatocellular carcinoma (HCC) HepG2 cell growth. However, theunderlying mechanisms remain unknown. Here, we evaluated the mechanisms of action of 1,8-cineole and thepotential benefits of its combination with anticancer compounds harboring ?anti-senescence? properties inHepG2 cells.Main methods: Cell viability was determined by the MTT assay. Cell cycle was assessed through flow cytometry(FC) and western blot (WB). Senescence was determined by the SA-β-galactosidase assay, and apoptosis bycaspase-3 activity, WB, and TUNEL. MAPKs (ERK, JNK, and p38), AMPK, and Akt/mTOR were analyzed by WB.Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were evaluated by FC andfluorescence microscopy.Key findings: 1,8-Cineole inhibited cell proliferation by promoting G0/G1 arrest. While 1,8-cineole was unable totrigger apoptosis, it induced cellular senescence. 1,8-Cineole promoted ROS production, ΔΨm depolarization,AMPK, ERK, and p38 activation and mTOR inhibition. Antioxidants, like N-acetyl-L-cysteine and vitamins,prevented HepG2 cell growth inhibition and senescence induced by 1,8-cineole. Pre-incubation with 1,8-cineolesensitized HepG2 cells to the anti-senescence compounds, quercetin, simvastatin, U0126, and SB202190.Combinations of 1,8-cineole and each compound synergistically inhibited cell viability, and combined treatmentwith 1,8-cineole and simvastatin induced apoptosis.Significance: 1,8-Cineole induces G0/G1 arrest and senescence in HepG2 cells through oxidative stress andMAPK, AMPK, and Akt/mTOR pathways, and sensitizes cells to anti-senescence drugs, suggesting that 1,8-cineolehas potential as an antineoplastic and adjuvant compound in combination with anti-senescence drugs inHCC therapy.