Design, Synthesis, and Biological Evaluation of Potent EZH2/LSD1 Dual Inhibitors for Prostate Cancer.

As histone modification enzymes, EZH2 mediates H3K27 trimethylation (H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and H3K9me1/2. Synergistic anticancer effects of combining inhibitors of these two enzymes are observed in leukemia and prostate cancer. Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized to evaluate their anticancer activity. After the structure-activity study, one of the best compounds, ML234, displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of ML234 was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by ML234 were verified by Western blot analysis. More importantly, the compound remarkably suppressed the tumor growth and enhanced the therapeutic efficacy of clinical drug enzalutamide in the 22RV1 xenograft mouse model, indicating that it may have potential as an anticancer agent in prostate cancer.

Sleeve gastrectomy decreases high-fat diet induced colonic pro-inflammatory status through the gut microbiota alterations.

Background: High-fat diet (HFD) induced obesity is characterized with chronic low-grade inflammation in various tissues and organs among which colon is the first to display pro-inflammatory features associated with alterations of the gut microbiota. Sleeve gastrectomy (SG) is currently one of the most effective treatments for obesity. Although studies reveal that SG results in decreased levels of inflammation in multiple tissues such as liver and adipose tissues, the effects of surgery on obesity related pro-inflammatory status in the colon and its relation to the microbial changes remain unknown. Methods: To determine the effects of SG on the colonic pro-inflammatory condition and the gut microbiota, SG was performed on HFD-induced obese mice. To probe the causal relationship between alterations of the gut microbiota and improvements of pro-inflammatory status in the colon following SG, we applied broad-spectrum antibiotics cocktails on mice that received SG to disturb the gut microbial changes. The pro-inflammatory shifts in the colon were assessed based on morphology, macrophage infiltration and expressions of a variety of cytokine genes and tight junction protein genes. The gut microbiota alterations were analyzed using 16s rRNA sequencing. RNA sequencing of colon was conducted to further explore the role of the gut microbiota in amelioration of colonic pro-inflammation following SG at a transcriptional level. Results: Although SG did not lead to pronounced changes of colonic morphology and macrophage infiltration in the colon, there were significant decreases in the expressions of several pro-inflammatory cytokines including interleukin-1ß (IL-1ß), IL-6, IL-18, and IL-23 as well as increased expressions of some tight junction proteins in the colon following SG, suggesting an improvement of pro-inflammatory status. This was accompanied by changing populations of the gut microbiota such as increased richness of Lactobacillus subspecies following SG. Importantly, oral administrations of broad-spectrum antibiotics to delete most intestinal bacteria abrogated surgical effects to relieve colonic pro-inflammation. This was further confirmed by transcriptional analysis of colon indicating that SG regulated inflammation related pathways in a manner that was gut microbiota relevant. Conclusion: These results support that SG decreases obesity related colonic pro-inflammatory status through the gut microbial alterations.