Cao Zhijun, Wang Wenxin, Yang Zhongcheng, Liu Yuxia, Sun Lidan, Zhang Luyong, Li Zheng
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Bioorg Chem. 2024 Dec;153:107852. doi: 10.1016/j.bioorg.2024.107852. Epub 2024 Sep 29.
Irinotecan (CPT-11) is a widely utilized topoisomerase I inhibitor in the treatment of colorectal cancer and other malignant tumors. However, severe and even life-threatening dose-limiting toxicity-delayed diarrhea affects the clinical application of CPT-11. The standard treatment for CPT-11-induced delayed diarrhea is prompt use of loperamide (LPA), however LPA can also cause constipation, diarrhea and even intestinal obstruction and has a high failure rate. Carboxylesterase 2 (CES2) is the main enzyme in the intestinal transformation of CPT-11, which can convert CPT-11 into toxic metabolite SN-38 and produce intestinal toxicity. Inhibiting CES2 activity can block the hydrolysis process of CPT-11 in the intestine and reduce SN-38 accumulation. Additionally, Farnesoid X receptor (FXR) agonists have anti-inflammatory, anti-secretory, and protective functions on intestinal barrier integrity that could potentially alleviate diarrhea. In this study, we investigated for the first time the anti-delayed diarrhea effect of FXR agonists, and the first time identified LE-77 as a potent dual modulator that activates FXR and inhibits CES2 through high-throughput screening. In the CPT-11-induced delayed diarrhea model, LE-77 demonstrated a dual modulator mechanism by activating FXR and inhibiting CES2, thereby reducing the accumulation of SN-38 in the intestine, alleviating intestinal inflammation, preserving intestinal mucosal integrity, and ultimately alleviating delayed diarrhea.
伊立替康（CPT-11）是一种广泛应用于治疗结直肠癌和其他恶性肿瘤的拓扑异构酶I抑制剂。然而，严重甚至危及生命的剂量限制性毒性——延迟性腹泻影响了CPT-11的临床应用。CPT-11诱导的延迟性腹泻的标准治疗方法是迅速使用洛哌丁胺（LPA），然而LPA也会导致便秘、腹泻甚至肠梗阻，且失败率很高。羧酸酯酶2（CES2）是CPT-11肠道转化的主要酶，它可将CPT-11转化为有毒代谢产物SN-38并产生肠道毒性。抑制CES2活性可阻断CPT-11在肠道内的水解过程并减少SN-38的积累。此外，法尼酯X受体（FXR）激动剂对肠道屏障完整性具有抗炎、抗分泌和保护作用，可能减轻腹泻。在本研究中，我们首次研究了FXR激动剂的抗延迟性腹泻作用，并首次通过高通量筛选鉴定出LE-77是一种强效双调节剂，可激活FXR并抑制CES2。在CPT-11诱导的延迟性腹泻模型中，LE-77通过激活FXR和抑制CES2表现出双调节剂机制，从而减少肠道内SN-38的积累，减轻肠道炎症，维持肠黏膜完整性，并最终减轻延迟性腹泻。
