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1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs
- Source :
- Life sciences, Vol. 243, p. 117271 (2020)
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- 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, 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. 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 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. Key findings 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. Significance 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.
- Subjects :
- AMPK
0301 basic medicine
Senescence
Cell cycle checkpoint
Resting Phase, Cell Cycle
030226 pharmacology & pharmacy
Antioxidants
General Biochemistry, Genetics and Molecular Biology
Cell cycle arrest
03 medical and health sciences
MAPKs
0302 clinical medicine
Humans
Viability assay
General Pharmacology, Toxicology and Pharmaceutics
Protein kinase B
Cellular Senescence
PI3K/AKT/mTOR pathway
Hepatocellular carcinoma cells
8-Cineole
Eucalyptol
Dose-Response Relationship, Drug
Cell growth
Chemistry
TOR Serine-Threonine Kinases
G1 Phase
Ribosomal Protein S6 Kinases, 70-kDa
Cell Cycle Checkpoints
Hep G2 Cells
General Medicine
Akt/mTOR
Cell cycle
Oxidative Stress
030104 developmental biology
Enzyme Induction
Cancer research
Reactive Oxygen Species
Protein Kinases
Subjects
Details
- ISSN :
- 00243205
- Volume :
- 243
- Database :
- OpenAIRE
- Journal :
- Life Sciences
- Accession number :
- edsair.doi.dedup.....ea842e923a789f0c74fe1a999e2405d6