Xanthine oxidase-mediated oxidative stress promotes cancer cell-specific apoptosis.
Free Radic Biol Med
; 139: 70-79, 2019 08 01.
Article
em En
| MEDLINE
| ID: mdl-31103463
ABSTRACT
The natural compound Alternol was shown to induce profound oxidative stress and apoptotic cell death preferentially in cancer cells. In this study, a comprehensive investigation was conducted to understand the mechanism for Alternol-induced ROS accumulation responsible for apoptotic cell death. Our data revealed that Alternol treatment moderately increased mitochondrial superoxide formation rate, but it was significantly lower than the total ROS positive cell population. Pre-treatment with mitochondria-specific anti-oxidant MitoQ, NOX or NOS specific inhibitors had no protective effect on Alternol-induced ROS accumulation and cell death. However, XDH/XO inhibition by specific small chemical inhibitors or gene silencing reduced total ROS levels and protected cells from apoptosis induced by Alternol. Further analysis revealed that Alternol treatment significantly enhanced XDH oxidative activity and induced a strong protein oxidation-related damage in malignant but not benign cells. Interestingly, benign cells exerted a strong spike in anti-oxidant SOD and catalase activities compared to malignant cells after Alternol treatment. Cell-based protein-ligand engagement and in-silicon docking analysis showed that Alternol interacts with XDH protein on the catalytic domain with two amino acid residues away from its substrate binding sites. Taken together, our data demonstrate that Alternol treatment enhances XDH oxidative activity, leading to ROS-dependent apoptotic cell death.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Xantina Oxidase
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Apoptose
/
Superóxidos
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Células Epiteliais
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Compostos Heterocíclicos de 4 ou mais Anéis
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Antineoplásicos
Idioma:
En
Revista:
Free Radic Biol Med
Assunto da revista:
BIOQUIMICA
/
MEDICINA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos