1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs

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, the underlying mechanisms remain unknown. Here, we evaluated the mechanisms of action of 1...

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Bibliographic Details
Published in:Life sciences (1973) 2020-02, Vol.243, p.117271-117271, Article 117271
Main Authors: Rodenak-Kladniew, Boris, Castro, Agustina, Stärkel, Peter, Galle, Marianela, Crespo, Rosana
Format: Article
Language:English
Subjects:
1,8-Cineole
Acetylcysteine
AKT protein
Akt/mTOR
AMPK
Anticancer properties
Antioxidants
Antioxidants - pharmacology
Apoptosis
Caspase-3
Cell cycle
Cell cycle arrest
Cell Cycle Checkpoints - drug effects
Cell growth
Cell proliferation
Cell viability
Cellular manufacture
Cellular Senescence - drug effects
Cineole
Combined treatment
Depolarization
Dose-Response Relationship, Drug
Enzyme Induction
Essential oils
Eucalyptol - administration & dosage
Eucalyptol - pharmacology
Eucalyptus
Evaluation
Flow cytometry
Fluorescence
Fluorescence microscopy
G1 Phase - drug effects
Galactosidase
Growth inhibition
Hep G2 Cells
Hepatocellular carcinoma
Hepatocellular carcinoma cells
Humans
MAP kinase
MAPKs
Membrane potential
Mitochondria
Oxidative stress
Oxidative Stress - drug effects
Plants
Protein Kinases - biosynthesis
Quercetin
Reactive oxygen species
Reactive Oxygen Species - metabolism
Resting Phase, Cell Cycle - drug effects
Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Senescence
Simvastatin
TOR protein
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
Vitamins
β-Galactosidase
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Summary: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, the underlying mechanisms remain unknown. Here, we evaluated the mechanisms of action of 1,8-cineole and the potential benefits of its combination with anticancer compounds harboring “anti-senescence” properties in HepG2 cells. 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 by caspase-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 and fluorescence microscopy. 1,8-Cineole inhibited cell proliferation by promoting G0/G1 arrest. While 1,8-cineole was unable to trigger 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-cineole sensitized 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 treatment with 1,8-cineole and simvastatin induced apoptosis. 1,8-Cineole induces G0/G1 arrest and senescence in HepG2 cells through oxidative stress and MAPK, AMPK, and Akt/mTOR pathways, and sensitizes cells to anti-senescence drugs, suggesting that 1,8-cineole has potential as an antineoplastic and adjuvant compound in combination with anti-senescence drugs in HCC therapy. [Display omitted] •1,8-Cineole (CN) promotes G0/G1 cell cycle arrest and senescence in HepG2 cells.•CN induces AMPK, ERK and p38 kinases and suppresses mTOR/p70S6K pathway.•CN induces ROS which contribute to cell growth inhibition and senescence.•CN sensitizes cells to anticancer drugs harboring anti-senescence properties.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2020.117271