A Glutathione Activatable Ion Channel Induces Apoptosis in Cancer Cells by Depleting Intracellular Glutathione Levels.
Angew Chem Int Ed Engl
; 59(20): 7944-7952, 2020 05 11.
Article
em En
| MEDLINE
| ID: mdl-32048775
ABSTRACT
Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance. In this study, we describe a novel 2,4-nitrobenzenesulfonyl (DNS) protected 2-hydroxyisophthalamide system that exploits GSH for its activation into free 2-hydroxyisophthalamide forming supramolecular M+ /Cl- channels. Better permeation of the DNS protected compound into MCF-7 cells compared to the free 2-hydroxyisophthalamide and GSH-activatable ion transport resulted in higher cytotoxicity, which was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway. The GSH-activatable transport-mediated cell death was further validated in rat insulinoma cells (INS-1E); wherein the intracellular GSH levels showed a direct correlation to the resulting cytotoxicity. Lastly, the active compound was found to restrict the growth and proliferation of 3D spheroids of MCF-7 cells with efficiency similar to that of the anticancer drug doxorubicin.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Canais de Cloreto
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Espaço Intracelular
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Glutationa
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Índia