CBP/P300 Inhibitors Mitigate Radiation-Induced GI Syndrome by Promoting Intestinal Stem Cell-Mediated Crypt Regeneration

Pathogenesis and therapy of radiation enteritis with gut microbiota

“…The CBP and p300 protein family consists of cyclic-AMP response element-binding protein-binding protein (CBP) and E1A-binding protein (P300). CBP/P300 inhibitors promoted the regeneration of intestinal organoids in vitro and remitted radiation-induced gastrointestinal syndrome by delaying intestinal epithelial cell cycle progression (Rao et al, 2021) (Figure 4D). The green tea polyphenol (−)-epigallocatechin-3gallate administration significantly reduced radiation-induced intestinal mucosal injury by increasing the number of LGR5+ISCs and Ki67+ crypt cells, reversing radiation-induced gut dysbiosis, restoring the Firmicutes/Bacteroidetes ratio, and increasing the abundance of beneficial bacteria (Cai et al, 2022) (Figure 4E).…”

“…The CBP and p300 protein family consists of cyclic-AMP response element-binding protein-binding protein (CBP) and E1Abinding protein (P300). CBP/P300 inhibitors promoted the regeneration of intestinal organoids in vitro and remitted radiation-induced gastrointestinal syndrome by delaying intestinal epithelial cell cycle progression (Rao et al, 2021) (Figure 4). Sirtuin one inhibitors could be effective clinical countermeasures to mitigate gastrointestinal toxicity by increasing p53 acetylation and the stabilization of p53, and likely contributing to the survival of intestinal epithelial cells in postradiation (Fu et al, 2021).…”

“…Therefore, it has been used in intestinal radiation studies, and some studies have used patient-derived organoids as a means of pre-evaluating radiation reactivity (Hsu et al, 2022). Ex vivo 3D organoid cultures derived from mouse jejunum and human ileum and colon were used to examine the radio-mitigative effects of CBP/ P300 inhibitors (Rao et al, 2021).Transplanted colonic organoids were successfully transplanted onto the rectal mucosa of irradiated mice, reconstructing epithelial structure and integrity (Jee et al, 2021). Therefore, the development of organoids will contribute to the treatment of radiation enteritis.…”

Assay establishment and validation of a high-throughput organoid-based drug screening platform

“…The intestinal organoids were developed from mouse small intestinal crypts and cultured as described by Rao et al [20]. Briefly, mouse small intestinal fragments (about 4 cm) were isolated and washed with cold PBS with penicillin and streptomycin (15,Gibco).…”

“…The count and area of surviving organoids were measured on the fifth day after 8 Gy IR. Compared with the control group, the bFGF group [21,22], NAM group [23,24], and SGC group [20] had significantly more surviving organoids and larger fluorescent areas. Among the three radioprotective agents, SGC showed the strongest radioprotective effect, which was consistent with the previous work (Fig.…”