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Amentoflavone suppresses cell proliferation and induces cell death through triggering autophagy-dependent ferroptosis in human glioma.
- Source :
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Life sciences [Life Sci] 2020 Apr 15; Vol. 247, pp. 117425. Date of Electronic Publication: 2020 Feb 11. - Publication Year :
- 2020
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Abstract
- Aims: Glioma is the most common type of malignant tumor of the nervous system, and aggressiveness and recurrence are major obstacles for treatment. This study is designed to explore the effects of amentoflavone (AF) on glioma, and to investigate the underlying mechanism of the anti-cancer activities of AF.<br />Methods: Cell morphology was recorded under microscopy. Cell viability and cell death ratio were determined by CCK-8 assay and lactate dehydrogenase (LDH) release assay, respectively. Cell cycle progression was assessed by flow cytometry. The levels of iron, MDA (malondialdehyde), lipid ROS, and GSH (reduced glutathione) were assessed by ELISA kit. The cycle-related proteins, ferroptosis-related protein, autophagy-related protein, and the phosphorylation of AMPK, mTOR and p70S6K were analyzed by western blotting. The autophagic flux was observed by transfecting cells with mRFP-GFP-LC3 plasmids. The xenograft murine models were established to analyze the effects of amentoflavone in vivo. The immunohistochemistry assay was performed to analyze the expression of LC3B, Beclin1, ATG5, ATG7, and ferritin heavy chain (FTH).<br />Results: Our results showed that AF treatment led to reduction in cell viability and cell death. In addition, AF was found to block cell cycle progression in a dose-dependent manner in vitro. Following treatment with AF, the intracellular levels of iron, MDA, and lipid OS were increased, and the levels of GSH and the mitochondrial membrane potential were reduced. In addition, our results showed that AF promoted the autophagic by regulating autophagy-relevant proteins. Our results also showed that the autophagy-induction by AF was associated with regulation of AMPK/mTOR signaling. Mechanistically, the inhibition effects of AF on glioma cell were reversed by DFO, ferreostatin-1 as well as upregulation of FTH. Meanwhile, the FTH levels were increased by compound C and knockdown of ATG7. Moreover, both autophagy inhibitor Baf A1 and knockdown of ATG7 were able to compromising AF-induce ferroptosis and cell death. In vivo, the tumor growth was suppressed by AF in a dose-dependent manner. The level of MDA in the tumor tissue was increased while the level of GSH in tumor tissue was decreased by AF in a dose-dependent manner. Furthermore, the expression of LC3B, Beclin1, ATG5, ATG7 were increased, and the expression of FTH were decreased by AF in a dose-dependent manner in vivo. Conclusion These results demonstrate that AF triggered ferroptosis in autophagy-dependent manner. Our results suggest that AF has the potential to be considered as a novel treatment agent in glioma.<br />Competing Interests: Declaration of competing interest None.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- AMP-Activated Protein Kinase Kinases
Animals
Antineoplastic Agents pharmacology
Autophagy-Related Proteins metabolism
Beclin-1 metabolism
Biflavonoids pharmacology
Cell Line, Tumor
Cytochrome P-450 CYP3A Inhibitors pharmacology
Glioma metabolism
Glioma pathology
Humans
Membrane Potential, Mitochondrial drug effects
Mice, Inbred BALB C
Mice, Nude
Microtubule-Associated Proteins metabolism
Protein Kinases metabolism
Ribosomal Protein S6 Kinases, 70-kDa metabolism
TOR Serine-Threonine Kinases metabolism
Antineoplastic Agents therapeutic use
Autophagy drug effects
Biflavonoids therapeutic use
Cytochrome P-450 CYP3A Inhibitors therapeutic use
Ferroptosis drug effects
Glioma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0631
- Volume :
- 247
- Database :
- MEDLINE
- Journal :
- Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32057904
- Full Text :
- https://doi.org/10.1016/j.lfs.2020.117425