title: Irinotecan disrupts tight junction proteins within the gut : implications for chemotherapy-induced gut toxicity.
abstract: Chemotherapy for cancer causes significant gut toxicity, leading to severe clinical manifestations and an increased economic burden. Despite much research, many of the underlying mechanisms remain poorly understood hindering effective treatment options. Recently there has been renewed interest in the role tight junctions play in the pathogenesis of chemotherapy-induced gut toxicity. To delineate the underlying mechanisms of chemotherapy-induced gut toxicity, this study aimed to quantify the molecular changes in key tight junction proteins, ZO-1, claudin-1, and occludin, using a well-established preclinical model of gut toxicity. Female tumor-bearing dark agouti rats received irinotecan or vehicle control and were assessed for validated parameters of gut toxicity including diarrhea and weight loss. Rats were killed at 6, 24, 48, 72, 96, and 120 h post-chemotherapy. Tight junction protein and mRNA expression in the small and large intestines were assessed using semi-quantitative immunohistochemistry and RT-PCR. Significant changes in protein expression of tight junction proteins were seen in both the jejunum and colon, correlating with key histological changes and clinical features. mRNA levels of claudin-1 were significantly decreased early after irinotecan in the small and large intestines. ZO-1 and occludin mRNA levels remained stable across the time-course of gut toxicity. Findings strongly suggest irinotecan causes tight junction defects which lead to mucosal barrier dysfunction and the development of diarrhea. Detailed research is now warranted to investigate posttranslational regulation of tight junction proteins to delineate the underlying pathophysiology of gut toxicity and identify future therapeutic targets.
authors: School of Medical Sciences; University of Adelaide; Adelaide, SA Australia.
authors: Hannah R
authors: HR
authors: Wardill
authors: School of Medical Sciences; University of Adelaide; Adelaide, SA Australia.
authors: Joanne M
authors: JM
authors: Bowen
authors: School of Medicine; University of Adelaide; Adelaide, SA Australia.
authors: Noor
authors: N
authors: Al-Dasooqi
authors: School of Medical Sciences; University of Adelaide; Adelaide, SA Australia.
authors: Masooma
authors: M
authors: Sultani
authors: School of Medicine; University of Adelaide; Adelaide, SA Australia.
authors: Emma
authors: E
authors: Bateman
authors: School of Medical Sciences; University of Adelaide; Adelaide, SA Australia.
authors: Romany
authors: R
authors: Stansborough
authors: School of Medical Sciences; University of Adelaide; Adelaide, SA Australia.
authors: Joseph
authors: J
authors: Shirren
authors: School of Medical Sciences; University of Adelaide; Adelaide, SA Australia.
authors: Rachel J
authors: RJ
authors: Gibson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced / Q000473:pathology; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007420:Intestine, Large / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000077146:Irinotecan; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019108:Tight Junctions / Q000187:drug effects* / Q000473:pathology; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D062445:Claudin-1; D062793:Occludin; D062826:Zonula Occludens-1 Protein; D000077146:Irinotecan; D002166:Camptothecin
keywords: chemotherapy; claudin-1; gut toxicity; mucositis; occludin; pro-inflammatory cytokines; tight junctions; zonular-occludens-1