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Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP

ABSTRACT: Ensartinib, an approved ALK inhibitor, is used as the first-line therapy for advanced ALK-positive non-small cell lung cancer in China. Ensartinib shows superior efficacy to crizotinib in both systemic and intracranial disease and is prepared to be reviewed overseas. In future, more patients would benefit from it based on its efficacy. However, a high incidence of hepatotoxicity has been observed in clinic, which often demands dose reduction or discontinuation of the drug, hampering its overall efficacy. Hence, it is inevitably valuable to study the mechanism which would be benefit to overcome the ensartinib-induced hepatotoxicity. In addition, based on the toxicity model, it is well established to understand the process of drug-induced liver injury and hepatic function-related molecules. Our findings discovered the level and location of TXNIP in liver homeostasis regulatory, clarified the molecular mechanism for ensartinib-induced hepatotoxicity and identified rutin as a potential strategy for the first time. We find a novel mode of rutin in intervening ROS production and apoptosis by binding TXNIP. Our study is of great significance to the basic theories and clinical practice. And this work is of broad interest to the readers from drug discovery, hepatologists in this filed and biologists in redox homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249370 | GEO | 2024/05/29

REPOSITORIES: GEO

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Project description:Damage of the intestinal epithelial barrier by xenobiotics or reactive oxygen species and a dysregulated immune response are both factors involved in the pathogenesis of inflammatory bowel diseases (IBD). Curcumin and rutin are polyphenolic compounds known to have anti-oxidant and anti-inflammatory activities, but their mechanism(s) of action are yet to be fully elucidated. Mdr1a-/- mice spontaneously develop intestinal inflammation, predominantly in the colon, with pathology similar to IBD, so this mouse model is relevant for studying diet-gene interactions and potential effects of foods on remission or development of IBD. This study tested whether the addition of curcumin or rutin to the diet would alleviate colonic inflammation in mdr1a-/- mice. Using whole-genome microarrays, the effect of dietary curcumin on gene expression in colon tissue was also investigated. Twelve mice were randomly assigned to each of three diets; control (AIN-76A), control + 0.2% curcumin or control + 0.1% rutin and monitored from the age of 7 to 24 weeks. Curcumin, but not rutin, significantly reduced histological signs of colonic inflammation in mdr1a-/- mice. Microarray and pathway analyses suggested that the effect of dietary curcumin on colon inflammation could be via an up-regulation of xenobiotic metabolism and a down-regulation of pro-inflammatory pathways probably mediated by PXR and PPARï¡ activation of RXR. These results reveal the potential of global gene expression and pathway analyses to study and better understand the effect of foods in colonic inflammation. Experiment Overall Design: Twelve mice were randomly assigned to each of three diets; control (AIN-76A), control + 0â¢2% curcumin or control + 0â¢1% rutin and monitored from the age of 7 to 24 weeks. As only curcumin significantly reduced colonic HIS, comparison of the gene expression levels in colon was carried out using total RNA from colon tissue of four mdr1a-/- mice from the control group (high HIS) and four mdr1a-/- mice from the curcumin group (low HIS). A reference design with eight arrays was used for this comparison, where each individual RNA sample was hybridized in the array with the reference RNA, totalizing 4 biological replicates per treatment.

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Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP

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