Amitriptyline prevents CPT-11-induced early-onset diarrhea and colonic apoptosis without reducing overall gastrointestinal damage in a rat model of mucositis

Fakiha, Khloud G.; Coller, Janet K.; Logan, Richard M.; Gibson, Rachel J.; Bowen, Joanne M.

doi:10.1007/s00520-018-4511-8

Cited by 8 publications

(9 citation statements)

References 35 publications

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“…Work by others have shown similar protective effects using non-specific TLR4 antagonists. For example, a study by Fakiha et al reported that amitriptyline was able to prevent CPT-11-induced diarrhoea and colonic apoptosis in rats but did not see any protective effects in histological architecture in the intestinal tract [ 19 ]. Although not using a TLR4 antagonist, a study by Wardill et al found that TLR4 knock-out mice were protected against CPT-11-induced mucosal tissue injury in the small intestine and also displayed a reduction in CPT-11-induced diarrhoea [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…The lack of measurable changes may be due to the kinetics of cell death and halting of the cell cycle following chemotherapy exposure. Previous studies have shown that apoptosis may be an early indicator of intestinal damage with rates peaking at 6 h after administration of CPT-11 [ 5 , 19 ]. Although slightly slower than apoptosis, halting of the cell cycle and reduced proliferation is known to peak between 24 and 48 h after exposure to chemotherapy [ 19 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that apoptosis may be an early indicator of intestinal damage with rates peaking at 6 h after administration of CPT-11 [ 5 , 19 ]. Although slightly slower than apoptosis, halting of the cell cycle and reduced proliferation is known to peak between 24 and 48 h after exposure to chemotherapy [ 19 , 22 , 23 ]. Collectively, this may account for the lack of difference between the CPT-11 and combination groups where tissue was collected at 72 h. Conversely, this lack in difference may also suggest that TLR4 downstream signalling may not play a major role in apoptosis seen in GIM.…”

Section: Discussionmentioning

confidence: 99%

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Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Tam

Crame

Elz

et al. 2022

Cancer Chemother Pharmacol

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Introduction Gastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11. Methods 24 C57BL/6 mice received a vehicle, daily i.p. IAXO-102 (3 mg/kg), i.p. CPT-11 (270 mg/kg) or a combination of CPT-11 and IAXO-102. GIM was assessed using validated toxicity markers. At 72 h, colon and tumour tissue were collected and examined for histopathological changes and RT-PCR for genes of interest; TLR4, MD-2, CD-14, MyD88, IL-6, IL-6R, CXCL2, CXCR1, and CXCR2. Results IAXO-102 prevented diarrhoea in mice treated with CPT-11. Tumour volume in IAXO-102-treated mice was lower compared to vehicle at 48 h (P < 0.05). There were no differences observed in colon and tumour weights between the treatment groups. Mice who received the combination treatment had improved tissue injury score (P < 0.05) in the colon but did not show any improvements in cell proliferation or apoptotic rate. Expression of all genes was similar across all treatment groups in the tumour (P > 0.05). In the colon, there was a difference in transcript expression in vehicle vs. IAXO-102 (P < 0.05) and CPT-11 vs. combination (P < 0.01) in MD-2 and IL-6R, respectively. Conclusion IAXO-102 was able to attenuate symptomatic parameters of GIM induced by CPT-11 as well as reduce tissue injury in the colon. However, there was no effect on cell proliferation and apoptosis. As such, TLR4 activation plays a partial role in GIM development but further research is required to understand the specific inflammatory signals underpinning tissue-level changes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Tam

Crame

Elz

et al. 2022

Cancer Chemother Pharmacol

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“…As shown by Gibson et al, CPT-11 (175 mg/kg) caused no significant changes on the expression of TLR-2, TLR-4, TLR-5 and TLR-9 in jejunum and colon epithelial cells within 120 h in breast cancer-bearing rats; however, the expression of TLR-4 and TLR-5 significantly decreased in jejunal crypts of rats at 96 and 120 h [59]. Similarly, Fikiha et al observed that there were no significant changes in ileal TLR-2 and TLR-4 proteins within 96 h after CPT-11 (125 mg/kg) treatment [60]. However, Wong et al observed that when the frequency of CPT-11 treatment (75 mg/kg*4d) increased, the expression of TLR-9 was found enhanced by four times in the ileum of mice, although it still had no obvious effect on TLR-2 [61].…”

Section: Chemotherapeutic Drugs Affecting Expression Of Tlrsmentioning

confidence: 95%

Chemotherapy-Induced Intestinal Microbiota Dysbiosis Impairs Mucosal Homeostasis by Modulating Toll-like Receptor Signaling Pathways

Wei

Wen

Chen

2021

IJMS

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Chemotherapy-induced intestinal mucositis, a painful debilitating condition affecting up to 40–100% of patients undergoing chemotherapy, can reduce the patients’ quality of life, add health care costs and even postpone cancer treatment. In recent years, the relationships between intestinal microbiota dysbiosis and mucositis have drawn much attention in mucositis research. Chemotherapy can shape intestinal microbiota, which, in turn, can aggravate the mucositis through toll-like receptor (TLR) signaling pathways, leading to an increased expression of inflammatory mediators and elevated epithelial cell apoptosis but decreased epithelial cell differentiation and mucosal regeneration. This review summarizes relevant studies related to the relationships of mucositis with chemotherapy regimens, microbiota, TLRs, inflammatory mediators, and intestinal homeostasis, aiming to explore how gut microbiota affects the pathogenesis of mucositis and provides potential new strategies for mucositis alleviation and treatment and development of new therapies.

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“…CPT-11 (irinotecan) has been used to treat various types of cancer, such as leukemia, lung, breast, belly, vaginal sarcoma, and soft tissue sarcoma. CPT-11 intercalates between base pairs of DNA and locates the double helix in the lower groove (Chen et al., 2019 ; Fakiha et al., 2019 ; Fan et al., 2019 ; Si et al., 2019 ). CPT-11 intercalation blocks the development of the enzyme topoisomerase II, which winds DNA for transcription.…”

Section: Introductionmentioning

confidence: 99%

NIR triggered PLGA coated Au-TiO₂ core loaded CPT-11 nanoparticles for human papillary thyroid carcinoma therapy

Tong

et al. 2020

Drug Delivery

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MDR (multi-drug resistance) is one of the significant deterrents of effective chemotherapy for malignant growth. One of the powerful ways to deal with defeat of the MDR is to utilize inorganic nanoparticle-intervened tranquilize conveyance to build the medication aggregations in cancerous growth cells. In this work, we have developed the presentation that is accurately made of medication conveyance framework dependent on the TiO 2 nanoparticles stacked CPT-11 to defeat the thyroid malignancy cells. The synthesized nanoparticles are characterized by spectroscopy methods (UV–vis, XPS, SEM, TEM, and DLS). The TEM results suggested that the shape of PLGA-Au-TiO 2 @CPT-11 of nanoparticles is ∼250 nm. After successful synthesis, we have evaluated the MTT of PLGA-Au-TiO 2 @CPT-11 nanoparticles with and without NIR radiations. Further, the morphological changes were observed using various biochemical stainings, such as acridine orange and ethidium bromide (AO–EB) and nuclear staining through Hoechst-33258. Also, migration and cell invasion were examined. The results show that these PLGA-Au-TiO 2 @CPT-11 and PLGA-Au-TiO 2 @CPT-11 + NIR nanoparticles exhibited promising antimetastatic property and reduced the cell invasion activity in B-CPAP and FTC-133 thyroid cancer cell lines. Based on the above findings, these PLGA-Au-TiO 2 @CPT-11 and PLGA-Au-TiO 2 @CPT-11 + NIR nanoparticles can be used as a promising candidate for the malignant thyroid cells.

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Amitriptyline prevents CPT-11-induced early-onset diarrhea and colonic apoptosis without reducing overall gastrointestinal damage in a rat model of mucositis

Cited by 8 publications

References 35 publications

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Chemotherapy-Induced Intestinal Microbiota Dysbiosis Impairs Mucosal Homeostasis by Modulating Toll-like Receptor Signaling Pathways

NIR triggered PLGA coated Au-TiO₂ core loaded CPT-11 nanoparticles for human papillary thyroid carcinoma therapy

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Amitriptyline prevents CPT-11-induced early-onset diarrhea and colonic apoptosis without reducing overall gastrointestinal damage in a rat model of mucositis

Cited by 8 publications

References 35 publications

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity

Chemotherapy-Induced Intestinal Microbiota Dysbiosis Impairs Mucosal Homeostasis by Modulating Toll-like Receptor Signaling Pathways

NIR triggered PLGA coated Au-TiO2 core loaded CPT-11 nanoparticles for human papillary thyroid carcinoma therapy

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NIR triggered PLGA coated Au-TiO₂ core loaded CPT-11 nanoparticles for human papillary thyroid carcinoma therapy