3-Methyladenine-enhanced susceptibility to sorafenib in hepatocellular carcinoma cells by inhibiting autophagy.
Adenine
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Apoptosis
/ drug effects
Autophagy
/ drug effects
Carcinoma, Hepatocellular
/ drug therapy
Drug Synergism
Hep G2 Cells
Humans
Liver Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ administration & dosage
Sorafenib
/ administration & dosage
Journal
Anti-cancer drugs
ISSN: 1473-5741
Titre abrégé: Anticancer Drugs
Pays: England
ID NLM: 9100823
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
pubmed:
5
1
2021
medline:
15
12
2021
entrez:
4
1
2021
Statut:
ppublish
Résumé
As an effective targeted therapy for advanced hepatocellular carcinoma (HCC), sorafenib resistance has been frequently reported in recent years, with the activation of autophagy by cancer cells under drug stress being one of the crucial reasons. Sorafenib treatment could enhance autophagy in HCC cells and autophagy is also considered as an important mechanisms of drug resistance. Therefore, the inhibition of autophagy is a potential way to improve the sensitivity and eliminate drug resistance to restore their efficacy. To determine whether autophagy is involved in sorafenib resistance and investigate its role in the regulation of HepG2 cells' (an HCC cell line) chemosensitivity to sorafenib, we simultaneously treated HepG2 with sorafenib and 3-Methyladenine (3-MA) (a common autophagy inhibitor). First, by performing cell counting kit 8 cell viability assay, Hoechst 33342 apoptosis staining, and Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis kit detection, we found that both sorafenib and 3-MA effectively inhibitted the proliferative activity of HepG2 cells and induced their apoptosis to a certain extent. This effect was significantly enhanced after these two drugs were combined, which was also confirmed by the increased expression of apoptosis-related proteins. Subsequently, by using AAV-GFP-LC3 transfection methods and transmission electron microscopy, we found that both the number and activity of autophagosomes in HepG2 cells in sorafenib and 3-MA group were significantly reduced, suggesting that autophagy activity was inhibited, and this result was consistent with the expression results of autophagy-related proteins. Therefore, we conclude that 3-MA may attenuate the acquired drug resistance of sorafenib by counteracting its induction of autophagy activity, thus enhancing its sensitivity to advanced HCC therapy.
Identifiants
pubmed: 33395067
doi: 10.1097/CAD.0000000000001032
pii: 00001813-202104000-00004
pmc: PMC7952045
doi:
Substances chimiques
Protein Kinase Inhibitors
0
3-methyladenine
5142-23-4
Sorafenib
9ZOQ3TZI87
Adenine
JAC85A2161
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
386-393Informations de copyright
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.
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