Harnessing human colonoid-derived monolayers as an in vitro platform for investigating accumulation, toxicity, and pharmacodynamics of small molecules

Le résumé fourni par la source

The purpose of this study was to evaluate differentiated human colonoid-derived monolayers (hCDMs) as an in vitro platform for investigating small molecule accumulation, toxicity, and pharmacodynamics (PD), in comparison to Caco-2 monolayers. Differentiated hCDMs formed polarized monolayers with a physiological barrier function (332.1 ± 52.02 Ω × cm 2 ). In toxicity assays for drug-induced diarrhea, hCDMs demonstrated enhanced sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) erlotinib and gefitinib, evidenced by lower concentrations inducing 20% inhibition (IC 20 ) of cell viability and IC 20 /30× maximal plasma concentration ( C max ) ratios, and decreased sensitivity to SN-38, indicated by higher IC 20 and IC 20 /30× C max , compared to Caco-2 monolayers. Baseline eicosanome profiling showed that hCDMs provided a colon-like representation of the prostaglandin (PG) pathway, whereas Caco-2 monolayers displayed cancer-associated profiles, such as elevated PGF 2α and 15k PGF 2α . Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) revealed that celecoxib elicited a dose-dependent reduction in the abundance of a subset of PGs within hCDMs, an effect not observed in the Caco-2 system. In conclusion, hCDMs present a more physiologically relevant alternative to conventional Caco-2 monolayers for integrated studies of cellular accumulation, toxicity, and PD in the colon. Incorporating additional donors and a broader compound panel will further enhance understanding of the model’s clinical relevance. • hCDMs enable simultaneous assessment of small molecule accumulation, toxicity, and PD. • hCDMs are more sensitive to erlotinib- and gefitinib-induced toxicity than Caco-2 monolayers. • hCDMs show colon-like prostaglandin levels, in contrast to cancer-like Caco-2 profiles. • Celecoxib reduces selected prostaglandin abundance in hCDMs concentration-dependently. • Extra donors and a wider drug panel may offer deeper insight into clinical relevance.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.