Zhang Qiong, Jiang Feilong, Tao Jin, Wang Huaibi, Sun Mingling, He Yancheng, Lai Zonglang
Department of Oncology, Chongqing Municipal Hospital of Traditional Chinese Medicine, Chongqing, China.
Transl Cancer Res. 2022 Sep;11(9):3250-3259. doi: 10.21037/tcr-22-2145.
Irinotecan (also known as CPT-11) is a topoisomerase I inhibitor that is primarily used for the treatment of advanced colorectal cancer. CPT-11 and its active metabolite SN-38 can directly damage intestinal mucosal cells. In addition, CPT-11 can activate the Toll-like receptor 4 (TLR4) inflammasome/nuclear factor kappa-B p65 (NF-κB p65) pathway, ultimately leading to intestinal inflammation-related injury. Shu Bu Wenshen Guchang recipe (SBWGR) has the spleen and kidneys. Herein, we investigated the effects of SBWGR on intestinal injury and the TLR4/NF-κB signaling pathways in mice with CPT-11-induced delayed-type diarrhea, aiming to provide evidence for the treatment of CPT-11-induced delayed-type diarrhea.
Thirty tumor-bearing mice were divided into normal control, model control, octreotide, low dose SBWGR, and high dose SBWGR groups, with 6 mice in each group. After successful modelling of delayed diarrhea, the normal and model control groups were given equal amounts of saline for 5 consecutive days, and the other three groups gave the corresponding intra-drug administration. Body weight, tumor size, Chiu score, intestinal ischemia and reperfusion injury, and disease activity index (DAI) were recorded in each group. The levels of intestinal interleukin-1β (IL-1β), IL-18, and tumor necrosis factor-α (TNF-α) were measured by an enzyme-linked immunosorbent assay (ELISA). Intestinal TLR4 and NF-κB p65 levels were measured by reverse transcription-polymerase chain reaction (RT-PCR) and protein blotting.
The weight of octreotide and kidney was higher than the control group (P<0.05); The tumor volume comparison of the model control group, octreotide group, warm kidney intestine low dose group, and warm kidney intestine high dose group were not significantly different (P>0.05). Octreotide group, intestinal Chiu score, diarrhea score, DAI level, intestinal inflammatory cytokines, IL-1β, IL-18 and TNF-α intestinal level, intestinal TLR4, NF-κB p65 mRNA protein expression levels were significantly lower than those of the model control group (P<0.05), and the amount of the treatment group was increased (P<0.05).
SBWGR exerts a prominent protective effect on intestinal damage caused by CPT-11-induced delayed-type diarrhea, which may be achieved by inhibiting the activation of the intestinal TLR4/NF-κB signaling pathway.
伊立替康（也称为CPT-11）是一种拓扑异构酶I抑制剂，主要用于治疗晚期结直肠癌。CPT-11及其活性代谢产物SN-38可直接损伤肠黏膜细胞。此外，CPT-11可激活Toll样受体4（TLR4）炎性小体/核因子κB p65（NF-κB p65）通路，最终导致肠道炎症相关损伤。舒补温肾固肠方具有健脾补肾作用。在此，我们研究了舒补温肾固肠方对CPT-11诱导的迟发型腹泻小鼠肠道损伤及TLR4/NF-κB信号通路的影响，旨在为CPT-11诱导的迟发型腹泻的治疗提供依据。
将30只荷瘤小鼠分为正常对照组、模型对照组、奥曲肽组、舒补温肾固肠方低剂量组和舒补温肾固肠方高剂量组，每组6只。成功建立迟发型腹泻模型后，正常对照组和模型对照组连续5天给予等量生理盐水，其他三组给予相应药物干预。记录每组小鼠的体重、肿瘤大小、Chiu评分、肠缺血再灌注损伤及疾病活动指数（DAI）。采用酶联免疫吸附测定（ELISA）法检测肠道白细胞介素-1β（IL-1β）、IL-18和肿瘤坏死因子-α（TNF-α）水平。采用逆转录-聚合酶链反应（RT-PCR）和蛋白质印迹法检测肠道TLR4和NF-κB p65水平。
奥曲肽组和舒补温肾固肠方高剂量组体重高于对照组（P<0.05）；模型对照组、奥曲肽组、温肾固肠低剂量组和温肾固肠高剂量组肿瘤体积比较差异无统计学意义（P>0.05）。奥曲肽组、舒补温肾固肠方高剂量组肠道Chiu评分、腹泻评分、DAI水平、肠道炎性细胞因子IL-1β、IL-18和TNF-α肠道水平、肠道TLR4、NF-κB p65 mRNA及蛋白表达水平均显著低于模型对照组（P<0.05），且各治疗组上述指标均有所改善（P<0.05）。
舒补温肾固肠方对CPT-11诱导的迟发型腹泻所致肠道损伤具有显著保护作用，其机制可能是通过抑制肠道TLR4/NF-κB信号通路的激活实现的。
