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Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2016 Jun; Vol. 15 (6), pp. 1376-86. Date of Electronic Publication: 2016 Mar 29. - Publication Year :
- 2016
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Abstract
- Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (-/-) BALB/c mice weighing between 18 and 25 g (10-13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4(-/-billy) mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4(-/-billy) (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4(-/-billy) mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376-86. ©2016 AACR.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Agents, Phytogenic pharmacology
Apoptosis
Bacteria drug effects
Bacteria genetics
Camptothecin adverse effects
Camptothecin pharmacology
Feces microbiology
Female
Gastrointestinal Diseases genetics
Gastrointestinal Diseases metabolism
Gastrointestinal Microbiome drug effects
Gene Deletion
Gene Expression Regulation drug effects
Irinotecan
Mice
Mice, Inbred BALB C
Pain genetics
Pain metabolism
Sequence Analysis, DNA
Signal Transduction drug effects
Toll-Like Receptor 4 metabolism
Antineoplastic Agents, Phytogenic adverse effects
Camptothecin analogs & derivatives
Gastrointestinal Diseases chemically induced
Pain chemically induced
Toll-Like Receptor 4 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 15
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 27197307
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-15-0990