Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review.

Treatment with pharmacological drugs for colorectal cancer (CRC) remains unsatisfactory. A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs, creating an urgent issue. In this review, we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness.

Aryl hydrocarbon receptor as a DNA methylation reader in the stress response pathway.

The aryl hydrocarbon receptor (AhR) mediates various cellular responses upon exposure to exogenous and endogenous stress factors. In these responses, AhR plays a dual role as a stress sensor for detecting various AhR ligands and as a transcription factor that upregulates the expression of downstream effector genes, such as those encoding drug-metabolizing enzymes. As a transcription factor, it selectively binds to the unmethylated form of a specific sequence called the xenobiotic responsive element (XRE).

β-naphthoflavone-induced upregulation of expression is mediated by the preferential binding of aryl hydrocarbon receptor to unmethylated xenobiotic responsive elements.

Human cytochrome P450 1 (CYP1) enzymes are transcriptionally induced by specific xenobiotics through a mechanism that involves the binding of aryl hydrocarbon receptors (AhR) to target xenobiotic responsive element (XRE) sequences. To examine the effect of DNA methylation on the AhR-mediated pathway, reverse transcription-quantitative PCR analysis was performed. β-naphthoflavone (βNF)-induced expression was found to be potentiated by pre-treatment of human HepG2 liver cancer cells with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, but not HuH7 cells.

Recent Progress in Prediction Systems for Drug-induced Liver Injury Using In vitro Cell Culture.

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed.

Objective: In this study, recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as on the limitations of in vitro cell culture systems for DILI research, was carried out.

Methods: Information related to DILI was collected through a literature search of the PubMed database.