Irinotecan disrupts tight junction proteins within the gut

Wardill, Hannah R.; Bowen, Joanne M.; Al‐Dasooqi, Noor; Sultani, Masooma; Bateman, Emma; Stansborough, Romany L.; Shirren, Joseph; Gibson, Rachel J.

doi:10.4161/cbt.27222

Cited by 70 publications

(30 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This contrasts with oral mucositis caused by conventional high‐dose chemotherapy and for which the pathobiology has been studied for the past two decades (Fig. 2) 2, 6, 23, 24, 25, 26, 27. Insights into the mechanism of action of mTOR inhibitors and naturally occurring oral mucosal lesions such as recurrent aphthous ulceration may thus be valuable in informing future research directions involving mIAS.…”

Section: Phenotype Incidence and Pathobiology Of Mtor Inhibitor–assmentioning

confidence: 99%

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

et al. 2016

View full text Add to dashboard Cite

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state‐of‐the‐science regarding mTOR inhibitor‐associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2–78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR‐associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high‐dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

show abstract

Section: Phenotype Incidence and Pathobiology Of Mtor Inhibitor–assmentioning

confidence: 99%

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

et al. 2016

View full text Add to dashboard Cite

show abstract

“…identified reduced tyrosine phosphorylation and cytoplasmic redistribution of intestinal ZO‐1 protein following methotrexate (MTX) treatment . Further, downregulation in claudin‐1 and occludin have been identified in response to both MTX and irinotecan treatment . Most recently, significant decreases in ZO‐1, claudin‐2 and claudin‐4 expression, as well as ZO‐1/claudin‐4 interaction, have been identified in the small intestine of MTX‐treated rats.…”

Section: Chemotherapy Disrupts Mucosal Barrier Function and Intestinamentioning

confidence: 99%

“…Consequently, tight junction disruption drastically alters barrier function and intestinal permeability; hallmark traits of many gut pathological states. Molecular defects in intestinal tight junctions have been seen following chemotherapy treatment highlighting a potential role for the mucosal barrier in CIGT . Changes in mucosal barrier function have been implicated in the development of chemotherapy‐induced diarrhoea and bacterial translocation .…”

mentioning

confidence: 99%

“…Molecular defects in intestinal tight junctions have been seen following chemotherapy treatment highlighting a potential role for the mucosal barrier in CIGT. [24][25][26][27] Changes in mucosal barrier function have been implicated in the development of chemotherapy-induced diarrhoea and bacterial translocation. 28 Despite these initial findings, the mechanisms responsible for chemotherapy-induced tight junction disruption remain unclear.…”

mentioning

confidence: 99%

See 1 more Smart Citation

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

Wardill

Gibson

Logan

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

Chemotherapy‐induced gut toxicity is a major clinical and economic burden to oncology practice. The mechanisms responsible for its development are ill defined, hampering the development of therapeutic interventions. In light of newly published research foci and clinical practice guidelines in supportive care in cancer, there has been renewed interest in the role tight junctions play in the pathobiology of chemotherapy‐induced gut toxicity. Several preclinical studies have identified molecular defects in intestinal tight junctions following chemotherapy. Despite these findings, the mechanisms responsible for chemotherapy‐induced tight junction disruption remain unclear. Recent research has highlighted roles for toll‐like receptor 4 and protein kinase C signalling in the regulation of tight junctions. This critical review therefore aims to provide evidence linking toll‐like receptor 4 expression, protein kinase C activation and tight junction disruption and their relationship to clinical toxicity.

show abstract

“…The current understanding of the molecular mechanisms that drive gut toxicity has not yet lead to any advances in its treatment and thus, a better understanding of the underlying biology is required. Recent research has outlined emerging evidence implicating intestinal barrier injury and tight junction disruption in the development of gut toxicity (6,7), however few studies have investigated their regulation and involvement in diarrhea.…”

Section: Introductionmentioning

confidence: 99%

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Wardill

Bowen

Sebille

et al. 2016

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4−/−) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4−/− BALB/c mice and (ii) to characterize the secretory profile of the distal colon. Forty-two female wild-type and 42 Tlr4−/− BALB/c mice weighing between 18 and 25 g received a single 270 mg/kg [intraperitoneal (i.p.)] dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. The secretory profile of the distal colon, following carbachol and forksolin, was assessed using Ussing chambers at all time points. Tight junction integrity was assessed at 24 hours, when peak intestinal permeability and diarrhea were reported, using immunofluorescence, Western blotting, and RT-PCR. Irinotecan caused internalization of claudin-1 with focal lesions of ZO-1 and occludin proteolysis in the ileum and colon of wild-type mice. Tlr4−/− mice maintained phenotypically normal tight junctions. Baseline conductance, a measure of paracellular permeability, was increased in irinotecan-treated wild-type mice at 24 hours (53.19 ± 6.46 S/cm2; P = 0.0008). No change was seen in Tlr4−/− mice. Increased carbachol-induced chloride secretion was seen in irinotecan-treated wild-type and Tlr4−/− mice at 24 hours (wild-type: 100.35 ± 18.37 μA/cm2; P = 0.022; Tlr4−/−: 102.72 ± 18.80 μA/cm2; P = 0.023). Results suggest that TLR4-dependent claudin-1 internalization and secondary anion secretion contribute to irinotecan-induced diarrhea. Mol Cancer Ther; 15(11); 2767–79. ©2016 AACR.

show abstract

Irinotecan disrupts tight junction proteins within the gut

Cited by 70 publications

References 50 publications

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

TLR4/PKC‐mediated tight junction modulation: A clinical marker of chemotherapy‐induced gut toxicity?

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea

Contact Info

Product

Resources

About