1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42), a novel ALK inhibitor, induces apoptosis and protective autophagy in H2228 cells.
EML4-ALK
H2228 cells
ZX-42
autophagy
mitochondrial apoptosis
Journal
The Journal of pharmacy and pharmacology
ISSN: 2042-7158
Titre abrégé: J Pharm Pharmacol
Pays: England
ID NLM: 0376363
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
13
01
2020
accepted:
23
05
2020
pubmed:
1
7
2020
medline:
23
6
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
To examine the antiproliferative effects of 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42) on the echinoderm microtubule-associated protein-4/anaplastic lymphoma kinase fusion gene (EML4-ALK) positive lung cancer cell line H2228 and its underlying mechanism. The MTT assay was used to study the effect of ZX-42 on H2228 cell growth. Propidium iodide (PI) staining and Western blotting were used to investigate the cell cycle changes. ZX-42-induced cell apoptosis was determined using the Annexin V-FITC/PI (AV/PI) apoptotic assay kit, acridine orange/ethidium bromide (AO/EB) and Hoechst 33258 staining, Rhodamine 123 (Rh 123) fluorescence assay and Western blotting. ZX-42-induced reactive oxygen species (ROS) production was examined by ROS assay kit. Transmission electron microscope, monodansylcadaverine (MDC) staining and the AV/PI apoptotic assay kit were used to demonstrate the relationship between autophagy and apoptosis. ZX-42 had good cell viability inhibitory effect on H2228 cells. ZX-42 dramatically inhibited ALK and its downstream pathways. ZX-42 also blocked H2228 cell cycle at G1 phase and then induced apoptosis by activating the mitochondrial pathway. Next, ZX-42 induced the production of ROS, and antioxidant N-acetylcysteine (NAC) reduced ROS production and also decreased apoptotic rates. We also found that ZX-42 induced protective autophagy in H2228 cells. In summary, ZX-42 is a novel ALK inhibitor that significantly inhibits the cell viability of H2228 cells and ultimately induces apoptosis through the mitochondrial pathway, in which autophagy plays a protective role. Therefore, inhibition of autophagy might enhance the anti-cancer effect of ZX-42.
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
ALK protein, human
EC 2.7.10.1
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1370-1382Subventions
Organisme : National Natural Science Foundation of China
ID : 81872394
Organisme : National Natural Science Foundation of China
ID : 81673308
Organisme : Young and middle age backbone personnel training programme of Shenyang Pharmaceutical University
ID : ZQN2015003
Organisme : Liaoning BaiQianWan Talents Program
ID : 2016921065
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2020 Royal Pharmaceutical Society.
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