Protective effect of curcumin against irinotecan-induced intestinal mucosal injury via attenuation of NF-KB activation, oxidative stress and endoplasmic reticulum stress

Irinotecan (CPT-11) is a DNA topoisomerase I inhibitor which is widely used in clinical chemotherapy, particularly for colorectal cancer treatment. However, late-onset diarrhea is one of the severe side-effects of this drug and this restricts its clinical application. The present study aimed to investigate the protective effects of curcumin treatment on CPT-11-induced intestinal mucosal injury both in vitro and in vivo and to elucidate the related mechanisms involved in these effects. For this purpose, mice were intraperitoneally injected with CPT-11 (75 mg/kg) for 4 days to establish a model of late-onset diarrhea. Curcumin (100 mg/kg) was intragastrically administered 8 days before the injection of CPT-11. Injury to small intestinal tissues was examined by H&E staining. The protein expression of prolyl 4-hydroxylase subunit beta (P4HB) and peroxiredoxin 4 (PRDX4) was detected by immunohistochemistry, as well as western blot analysis. IEC-6 cell viability was detected by MTT assay. Flow cytometry was performed to examine the cell apoptotic rate, mitochondrial membrane potential and reactive oxygen species (ROS) generation. Immunofluorescence was used to observe the localization of nuclear factor (NF)-KB. The levels of cleaved caspase-3, glucose-regulated protein, 78 kDa (GRP78), P4HB, PRDX4 and CHOP were detected by western blot analysis. The results revealed that in vivo, curcumin effectively attenuated the symptoms of diarrhea and abnormal intestinal mucosa structure induced by CPT-11 in nude mice. Treatment with curcumin also increased the expression of P4HB and PRDX4 in the tissue of the small intestine. In vitro, curcumin, exhibited little cytotoxicity when used at concentrations