Side Effects Of Cancer Chemotherapy Research Articles

Abstract 5746: Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs

Abstract Triptorelin® (TRP) is an anti-cancer drug used for the treatment of a wide range of hormone-responsive cancers, including prostate cancer. The increase in testosterone levels, known as the flare effect, is a major side effect of cancer chemotherapy when TRP is used in a combination regimen. Reports indicate that enhancing the cellular uptake and retention of TRP can improve its biological activity. In this study, TRP conjugates of tris(4-methoxyphenyl) methanol derivatives (TPMs) with optimized hydrophobicity were synthesized by reacting 2-substituted methoxybenzenes with 1,3,5-trioxane, followed by conjugation with TRP and sebacic acid to produce TRP-TPMs derivatives. The hydrophobicity of TRP was optimized by using the appropriate hydrophobic linker attached to the respective TPM to improve cellular uptake. The aim of the current studies was to evaluate the respective antiproliferative effects of the newly synthesized TRP-TPMs, physical mixtures of TPMs and TRP using different cell lines. Our hypothesis was that exposure of cells to TRP-TPMs derivatives can enhance the antiproliferative activities in cells in comparison to respective the physical mixtures and TRP. Antiproliferative studies in human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse preadipocytes (3T3-L1) were carried out following exposure to the respective compounds. Our findings indicate that TRP-TPMs conjugates, at a concentration of 50 µM, significantly inhibited cell proliferation in CCRF-CEM, SK-OV-3, and 3T3-L1 cells by 21-37%, 24-73%, and 37-56%, respectively, following 72-hour incubation in comparison to the respective physical mixtures and TRP. Conjugation of TRP with the respective derivative of TPMs enhanced antiproliferative activities in all the cells (with no significant differences in cytotoxicity) compared to the physical mixtures of TPMs and TRP. The findings in the current studies suggest that TRP-TPMs can be used as potential prodrugs, to enhance the cells biological activity, and cellular uptake of TRP. Citation Format: Ryan Beni, William Boadi, Jawzah Alnakhli, Samiyah Alhamed. Tris(4-methoxyphenyl) methanol conjugates of triptorelin as cell-penetrating anti-cancer prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5746.

Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics, however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA-Seq, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe OHC loss and progressive damage of synapses in IHC were observed in Atoh1-Gpx4-/- mice. However, Fsp1-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of Transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.

Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure.

Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro-oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

A novel thermoresponsive nano carrier matrix of hyaluronic acid, methotrexate and chitosan to target the cluster of differentiation 44 receptors in tumors

Major challenges in current cancer chemotherapy include drug resistance, low efficacy and non-selectivity, resulting in undesirable side effects. In this study, we demonstrate a solution to these challenges that involves a dual targeting approach for tumors that overexpress CD44 receptors. The approach employs a nano-formulation (tHAC-MTX nano assembly), fabricated from hyaluronic acid (HA), the natural ligand for CD44, conjugated with methotrexate (MTX) and complexed with the thermoresponsive polymer 6-O-carboxymethylchitosan (6-OCMC) graft poly(N-isopropylacrylamide) [6-OCMC-g-PNIPAAm]. The thermoresponsive component was designed to have a lower critical solution temperature of 39 °C (the temperature of tumor tissues). In-vitro drug release studies reveal faster release of the drug at the higher temperatures of the tumor tissue likely due to the conformation changes in the thermoresponsive component of the nano assembly. Drug release was also enhanced in the presence of hyaluronidase enzyme. Higher cellular uptake and greater cytotoxicity of the nanoparticles were demonstrated in cancer cells that overexpress CD44 receptors suggesting a receptor binding and cellular uptake mechanism. Such nano-assemblies which incorporate multiple targeting mechanisms have the potential to improve efficacy and decrease side effects of cancer chemotherapy.

D2 Receptors and Sodium Ion Channel Blockades of the Basolateral Amygdala Attenuate Lithium Chloride-Induced Conditioned Taste Aversion Applying to Cancer Chemotherapy Nausea and Vomiting

Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.

Assessing the Knowledge Regarding Common Side-Effects of Cancer Chemotherapy among Patients Attending NEIGRIHMS, Shillong with a View of Improving Current Practices - A Cross Sectional Study

Assessing the Knowledge Regarding Common Side-Effects of Cancer Chemotherapy among Patients Attending NEIGRIHMS, Shillong with a View of Improving Current Practices - A Cross Sectional Study

Development and Application of Indolines in Pharmaceuticals.

In recent years, the incidence of cancer is high around the world, and the resistance of bacteria is increasing. To cope with the potentially adverse side effects of cancer chemotherapy and surgery, researchers are turning to the construction of new drug scaffolds. The indoline structure exists in a huge number of natural products, but drugs with indoline have only been formally studied in recent years. With the deepening of research, drugs containing indoline have played important roles in more disease treatment aspects, such as anti-tumor, anti-bacterial, anti-inflammatory and have been used as analgesics, to treat cardiovascular diseases and so on. The synthesis and pharmacological activity of indoline derivatives is summarized in this review in order to support the addition of the indoline component to the toolbox of medicinal chemists. This review focuses on the advantages of indoline compounds in development and synthesis of and for the use as anticancer drugs, antibacterial drugs, to treat cardiovascular diseases and as anti-inflammatory and analgesic drugs. Indoline structures are commonly found in natural and synthetic compounds with medicinal value and are now beginning to be exploited as the basic backbone of various drugs. As research continues, dihydroindoles and their derivatives will play a greater role in the medical field.

PET/CT imaging detects intestinal inflammation in a mouse model of doxorubicin-induced mucositis.

A severe side effect of cancer chemotherapy is the development of gastrointestinal mucositis, characterised by mucosal inflammation. We investigated if 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography combined with computed tomography (2-[18F]FDG-PET/CT) could visualise gastrointestinal mucositis in mice treated with the chemotherapeutic agent doxorubicin. In this study, gastrointestinal inflammation was longitudinally evaluated by 2-[18F]FDG-PET/CT scans before and 1, 3, 6, and 10 days after treatment with doxorubicin. Doxorubicin-treated mice were compared to saline-treated littermates using the abdominal standard uptake value of 2-[18F]FDG corrected for body weight (SUVBW). Abdominal SUVBW was significantly increased on day 1 (p < 0.0001), day 3 (p < 0.0001), and day 6 (p < 0.05) in the doxorubicin-treated group compared to controls. Abdominal SUVBW returned to baseline levels on day 10. In the doxorubicin group, the largest weight loss was observed on day 3 (control vs doxorubicin, mean percent of baseline weight: (98.5 ± 3.2% vs 87.9 ± 4.6%, p < 0.0001). Moreover, in the doxorubicin-treated group, villus lengths were decreased by 23-28% on days 1 and 3 in the small intestine (p < 0.05), and jejunal levels of tumour necrosis factor and interleukin-1β were significantly increased on day 3 (p < 0.05). Together, these findings indicate that sequential 2-[18F]FDG-PET/CT scans can objectively quantify and evaluate the development and resolution of intestinal inflammation over time in a mouse model of doxorubicin-induced mucositis.

Biomedical gastronomy in the interventions of smell and taste disorders in ‘altered eating’

Biomedical gastronomy in the interventions of smell and taste disorders in ‘altered eating’

A Comprehensive Review on Nutraceuticals: Therapy Support and Formulation Challenges.

Nutraceuticals are the nourishing components (hybrid of nutrition and pharmaceuticals) that are biologically active and possess capability for maintaining optimal health and benefits. These products play a significant role in human health care and its endurance, most importantly for the future therapeutic development. Nutraceuticals have received recognition due to their nutritional benefits along with therapeutic effects and safety profile. Nutraceuticals are globally growing in the field of services such as health care promotion, disease reduction, etc. Various drug nutraceutical interactions have also been elaborated with various examples in this review. Several patents on nutraceuticals in agricultural applications and in various diseases have been stated in the last section of review, which confirms the exponential growth of nutraceuticals' market value. Nutraceuticals have been used not only for nutrition but also as a support therapy for the prevention and treatment of various diseases, such as to reduce side effects of cancer chemotherapy and radiotherapy. Diverse novel nanoformulation approaches tend to overcome challenges involved in formulation development of nutraceuticals. Prior information on various interactions with drugs may help in preventing any deleterious effects of nutraceuticals products. Nanotechnology also leads to the generation of micronized dietary products and other nutraceutical supplements with improved health benefits. In this review article, the latest key findings (clinical studies) on nutraceuticals that show the therapeutic action of nutraceutical's bioactive molecules on various diseases have also been discussed.

PD-L1-Targeted Co-Delivery of Two Chemotherapeutics for Efficient Suppression of Skin Cancer Growth.

To overcome the severe side effects of cancer chemotherapy, it is vital to develop targeting chemotherapeutic delivery systems with the potent inhibition of tumour growth, angiogenesis, invasion and migration at low drug dosages. For this purpose, we co-loaded a conventional antiworm drug, albendazole (ABZ), and a TOPK inhibitor, OTS964, into lipid-coated calcium phosphate (LCP) nanoparticles for skin cancer treatment. OTS- and ABZ-loaded LCP (OTS-ABZ-LCP) showed a synergistic cytotoxicity against skin cancer cells through their specific cancerous pathways, without obvious toxicity to healthy cell lines. Moreover, dual-targeting the programmed death ligand-1 (PD-L1) and folate receptor overexpressed on the surface of skin cancer cells completely suppressed the skin tumour growth at low doses of ABZ and OTS. In summary, ABZ and OTS co-loaded dual-targeting LCP NPs represent a promising platform with high potentials against complicated cancers where PD-L1/FA dual targeting appears as an effective approach for efficient and selective cancer therapy.

The potential role of prebiotics, probiotics, and synbiotics in adjuvant cancer therapy especially colorectal cancer.

Cancer is a global health issue that is rising swiftly with younger people and an increased number of patients. The role of human microbiota in the pathophysiology of tumors has been paid more and more attention. Microecologics including prebiotics, probiotics, and synbiotics are among the best validated/proven resources for the application of microbiological prophylaxis and therapy. There is strong evidence that microecologics have anti-cancer activity and their potential association with cancer is significant. In this review, we will focus on the role of prebiotics, probiotics, and synbiotics in tumor suppression in maintaining the colon barrier, metabolism, immune regulation, inhibition of host tumor cell proliferation, and epidemiological-based recommendations. Besides, other signs illuminate the role of microecological agents to adjunct the cancer treatment and counter the toxic side effects of cancer drugs. In addition, we will explore their role in chemotherapy, where these probiotics can be used as an adjunct to chemotherapy, counteracting the toxic side effects of chemotherapy drugs to minimize or optimize the therapeutic effect. In the treatment of cancer, we can see the role of prebiotics, probiotics, synbiotics, and their application in cancer patients, and the effectiveness effect can be considered as a clinical benefit. PRACTICAL APPLICATIONS: A large number of studies have shown that microecologics including prebiotics, probiotics, and synbiotics play an important role in regulating intestinal microecology and contribute to the prevention and treatment of cancer, indicating that prebiotics, probiotics, and synbiotics have the potential to be used as microecological modulators in the adjuvant therapy of cancer. However, it is not clear what is the anti-tumor mechanism of these microecologics and how they antagonize the side effects of cancer chemotherapy and protect normal cells. This paper reviews the role of prebiotics, probiotics, and synbiotics in tumor suppression in maintaining the colon barrier, metabolism, immune regulation, and prevention of rapid growth of host cells, as well as their potential role in cancer chemotherapy. This review helps to better understand the relationship between prebiotics, probiotics, and synbiotics with immune regulation, intestinal microecology, metabolic regulation, and cell proliferation and provides strong evidence for their potential application as microecologics in cancer adjuvant therapy.

Persistent red blood cells retain their ability to move in microcapillaries under high levels of oxidative stress

Oxidative stress is one of the key factors that leads to red blood cells (RBCs) aging, and impairs their biomechanics and oxygen delivery. It occurs during numerous pathological processes and causes anaemia, one of the most frequent side effects of cancer chemotherapy. Here, we used microfluidics to simulate the microcirculation of RBCs under oxidative stress induced by tert-Butyl hydroperoxide. Oxidative stress was expected to make RBCs more rigid, which would lead to decrease their transit velocity in microfluidic channels. However, single-cell tracking combined with cytological and AFM studies reveals cell heterogeneity, which increases with the level of oxidative stress. The data indicates that the built-in antioxidant defence system has a limit exceeding which haemoglobin oxidation, membrane, and cytoskeleton transformation occurs. It leads to cell swelling, increased stiffness and adhesion, resulting in a decrease in the transit velocity in microcapillaries. However, even at high levels of oxidative stress, there are persistent cells in the population with an undisturbed biophysical phenotype that retain the ability to move in microcapillaries. Developed microfluidic analysis can be used to determine RBCs’ antioxidant capacity for the minimization of anaemia during cancer chemotherapy.

A Review of Some Treatments for Oral Mucositis Induced by Using 5-Fluorouracil

Oral mucositis (OM) remain the principal complication and costly side effect of cancer chemotherapy. It is creating progressively important contribution to mortality rate as the clinical manifestation ranging from moderate including pain and impairs food and drink ingestion to sever mucosal lesion which developed to life threading due to intense immune suppression. 5-Fluorouracil (5-FU) is a pyrimidine analogue which considered as a vital treatment for diversified shapes of solid tumors for over 40 years. Intravenous (IV) route of 5-Fluorouracil medication treating are commonly used. Experimental studies had demonstrated that the uracil was necessary for sustaining nucleic acid synthesis required for tumor growth, this led to hypothesis the 5-flurauracil might interfere with nucleic acid synthesis and slow tumor growth. Use of 5-FU drug is one of the most common causes of OM. Our review demonstrates and cooperate the drugs and beside diminish riskiness of chemotherapy 5-FU as a causes of OM in experimental animal.

On the receiving end: have patient perceptions of the side-effects of cancer chemotherapy changed since the twentieth century?

BackgroundStudies in 1983 and 1993 identified and ranked symptoms experienced by cancer patients receiving chemotherapy. We repeated the studies to obtain updated information on patient perceptions of chemotherapy-associated symptoms.Patients and methodsA cross-sectional interview and patient-reported outcome questionnaires were administered to out-patients receiving chemotherapy. Patients selected from 124 cards to identify and rank the severity of physical and non-physical symptoms they had experienced and attributed to chemotherapy (primary endpoint). The patient’s medical oncologist and primary chemotherapy nurse were invited to rank the five symptoms they believed the patient would rank as their most severe. We analysed the association of symptoms and their severity with patient demographics, chemotherapy regimen, and patient-reported outcomes. Results were compared to the earlier studies.ResultsOverall, 302 patients completed the interview: median age 58 years (range 17–85); 56% female; main tumour types colorectal 81 (27%), breast 67 (22%), lung 49 (16%); 45% treated with curative intent. Most common symptoms (reported by >50%) were: alopecia, general weakness, effects on family/partner, loss of taste, nausea, fatigue, difficulty sleeping, effects on work/home duties, and having to put life on hold. The most severe symptoms (ranked by >15% in top five) were: concern about effects on family/partner, nausea, fear of the future, fatigue, not knowing what will happen, putting my life on hold, and general weakness. Perceptions of doctors and nurses of patients’ symptom severity closely matched patients’ rankings.ConclusionsCompared to earlier studies, there was an increase in non-physical concerns such as effects on family and future, and a decrease in physical symptoms, particularly vomiting, but nausea, fatigue and general weakness remained bothersome.Highlights• Symptoms related to chemotherapy have changed over time, likely due to less toxic regimens and improvements in supportive care.• Effects on family/partner, fear of the future, not knowing what will happen, and “life on hold” were major issues for patients.• Vomiting has decreased but nausea, fatigue and general weakness remain common symptoms for chemotherapy patients.

The golden spice curcumin in cancer

Curcumin, the key bioactive phytochemical present in turmeric (Curcuma longa L.), is the most studied natural compound in cancer. Preclinical studies (in vitro and in vitro) and clinical trials have demonstrated curcumin's effectiveness as an anti-inflammatory agent. The existing evidence supports that curcumin inhibits the proliferation of many types of cancer cells and can play an important role in cancer therapy. This study analyses the existing evidence in the literature on finalized clinical trials (2010-2020) related to the effect of curcumin and turmeric-derived products that focused on different types of cancers, such as chronic myeloid leukemia, multiple myeloma, prostate, colorectal and pancreatic cancer as well as cancer therapy-related complications, including oral mucositis and radiation dermatitis. Original English language articles and clinical trials published between 2010 and 2020 were searched using mainstream scholarly databases, such as PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov. The keywords, such as "curcumin," "turmeric," "cancer," "anti-inflammatory," and "clinical trials," were used in various combinations. A total of 21 clinical trials were selected, reviewed, and included in this study. Sixteen out of 21 clinical trials were associated with the effectiveness of curcumin or turmeric on various types of cancer, and the other five clinical trials were related to the evaluation of the efficacy of curcumin or turmeric in relieving the side effects of cancer chemotherapy and radiotherapy. The emerging data from the clinical trials confirm that curcumin has the potential for cancer prevention and intervention. However, it is not yet clear whether long-term curcumin supplementation has similar benefits.

Development of new treatments based on commercial medicines for side effects in cancer chemotherapy

Development of new treatments based on commercial medicines for side effects in cancer chemotherapy

Microfluidic Characterization of Red Blood Cells Microcirculation under Oxidative Stress.

Microcirculation is one of the basic functional processes where the main gas exchange between red blood cells (RBCs) and surrounding tissues occurs. It is greatly influenced by the shape and deformability of RBCs, which can be affected by oxidative stress induced by different drugs and diseases leading to anemia. Here we investigated how in vitro microfluidic characterization of RBCs transit velocity in microcapillaries can indicate cells damage and its correlation with clinical hematological analysis. For this purpose, we compared an SU-8 mold with an Si-etched mold for fabrication of PDMS microfluidic devices and quantitatively figured out that oxidative stress induced by tert-Butyl hydroperoxide splits all RBCs into two subpopulations of normal and slow cells according to their transit velocity. Obtained results agree with the hematological analysis showing that such changes in RBCs velocities are due to violations of shape, volume, and increased heterogeneity of the cells. These data show that characterization of RBCs transport in microfluidic devices can directly reveal violations of microcirculation caused by oxidative stress. Therefore, it can be used for characterization of the ability of RBCs to move in microcapillaries, estimating possible side effects of cancer chemotherapy, and predicting the risk of anemia.

Aprepitant Promotes Caspase-Dependent Apoptotic Cell Death and G2/M Arrest through PI3K/Akt/NF-κB Axis in Cancer Stem-Like Esophageal Squamous Cell Carcinoma Spheres.

The antagonists of the neurokinin-1 receptor (NK1R) are known for their anti-inflammatory, anxiolytic, antiemetic, and anticancer activities. Aprepitant, a nonpeptide NK1R antagonist, is used in nausea and vomiting, the most common side effects of cancer chemotherapy in patients. It has been established that NK1R activation by substance P (SP), which links cancer promotion and progression to a neurokinin-mediated environment, became one mechanism that corresponds to the mitogenesis of tumor cells. Therefore, this study is aimed at explaining and evaluating the anticancer impacts of aprepitant on esophageal squamous cancer cell (ESCC) spheres by using in vitro experiments, such as resazurin, ROS, annexin-V binding, RT-PCR, and Western blot analysis. As a result, we showed that aprepitant had strong antiproliferative and cytotoxic effects on ESCC cell spheres. Also, aprepitant caused significant G2-M cell cycle arrest depending on concentration increase. Further, exposure of cells to this agent resulted in caspase -8/-9-dependent apoptotic pathway activation by modifying the expression of genes involved in apoptosis. Besides, treatment of the cells by aprepitant abrogates of the PI3K/Akt pathway, as shown by reducing the level of Akt, induces apoptotic cell death. In summary, pharmacological inhibition of NK1R with aprepitant seems to have a significant chance of treating ESCC as a single agent or in conjunction with other chemotherapeutic drugs.

Knockdown of TRIM9 attenuates irinotecan‑induced intestinal mucositis in IEC‑6 cells by regulating DUSP6 expression via the P38 pathway.

Intestinal mucositis is a common side effect of cancer chemotherapy and it limits the dose of chemotherapy given to a patient. Tripartite motif family (TRIM) proteins have been reported to be implicated in the regulation of cancer chemotherapy. The present study aimed to investigate the effect of TRIM9 on irinotecan-induced intestinal mucositis in the rat intestinal epithelial cell line IEC-6. The expression of several TRIMs, such as TRIM1, TRIM9, TRIM18, TRIM36, TRIM46 and TRIM67, was examined. After TRIM9 knockdown or overexpression by lentivirus infection, cell proliferation and apoptosis, epithelial barrier tight-junction proteins, inflammatory cytokines, transepithelial electrical resistance (TEER) and FITC dextran were measured. Treatment with irinotecan significantly inhibited cell proliferation and induced cell apoptosis, TRIM9 expression, intestinal mucosal barrier impairment, the levels of inflammatory cytokines and P38 phosphorylation in IEC-6 cells, while the expression levels of epithelial barrier tight-junction protein ZO-1 and Claudin-4 were decreased. Knockdown of TRIM9 partly counteracted the effect of irinotecan treatment, and inhibition of P38 potently reversed the effect of TRIM9 overexpression in IEC-6 cells. Moreover, co-immunoprecipitation showed an interaction between TRIM9 and DUSP6 in IEC-6 cells, and overexpression of DUSP6 notably counteracted the effect of TRIM9 overexpression. The results demonstrated that TRIM9 knockdown may benefit patients with intestinal mucositis by inhibiting inflammatory cytokine expression and repairing intestinal barrier functions, which was probably due to inhibition of the activation of the P38 pathway via targeting DUSP6.