1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs.
Antioxidants
/ pharmacology
Cell Cycle Checkpoints
/ drug effects
Cellular Senescence
/ drug effects
Dose-Response Relationship, Drug
Enzyme Induction
Eucalyptol
/ administration & dosage
G1 Phase
/ drug effects
Hep G2 Cells
Humans
Oxidative Stress
/ drug effects
Protein Kinases
/ biosynthesis
Reactive Oxygen Species
/ metabolism
Resting Phase, Cell Cycle
/ drug effects
Ribosomal Protein S6 Kinases, 70-kDa
/ antagonists & inhibitors
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
1,8-Cineole
AMPK
Akt/mTOR
Cell cycle arrest
Hepatocellular carcinoma cells
MAPKs
Oxidative stress
Senescence
Journal
Life sciences
ISSN: 1879-0631
Titre abrégé: Life Sci
Pays: Netherlands
ID NLM: 0375521
Informations de publication
Date de publication:
15 Feb 2020
15 Feb 2020
Historique:
received:
30
08
2019
revised:
26
12
2019
accepted:
03
01
2020
pubmed:
12
1
2020
medline:
27
2
2020
entrez:
12
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31926243
pii: S0024-3205(20)30018-7
doi: 10.1016/j.lfs.2020.117271
pii:
doi:
Substances chimiques
Antioxidants
0
Reactive Oxygen Species
0
Protein Kinases
EC 2.7.-
MTOR protein, human
EC 2.7.1.1
Ribosomal Protein S6 Kinases, 70-kDa
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Eucalyptol
RV6J6604TK
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
117271Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that there are no conflicts of interest.