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INTRODUCTION: 5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat various types of cancers. Although widely used, it has consistently been attributed to cardiotoxicities after administration. The purpose of this study was to assess the parameters and predictors of cardiotoxicities associated with various 5-FU-based chemotherapeutic protocols in patients with GI/colorectal cancer, as well as the correlation of these cardiotoxic events with age, sex, cumulative dose, and risk factors such as obesity, hypertension, and family history of cardiac diseases. METHODS: A prospective study consisting of 396 patients of both sexes was conducted in the oncology ward of Nishtar Hospital in Multan, Pakistan. Patients were grouped according to the therapeutic protocol they received (5-FU monotherapy or in combination, with different dosing regimens). Electrocardiography and serum troponin levels were used to assess 5-FU-induced cardiotoxicity. In cases where cardiotoxicity was detected, 5-FU treatment was interrupted; nitroglycerin, nitrates, and calcium channel blockers were administered; and cardiac monitoring was initiated. 5-FU was discontinued in all cases of acute myocardial infarction. RESULTS: Of the 396 patients, 28.5% reported different cardiotoxic symptoms after receiving various 5-FU-containing protocols. 35% had anginal pain, 13% suffered a myocardial infarction, 11% developed hypertension, and 10% presented heart failure. Patients receiving 5-FU combination therapy showed cardiotoxic events that were significantly different from those on 5-FU monotherapy. Based on the ECG results, only the QTc-d interval increased significantly (p < 0.001) after therapy. 68% of the patients had troponin levels > 2 ng/mL at the end of treatment. CONCLUSIONS: Pre-existing cardiac diseases, treatment duration, smoking, and obesity were found to be influential components in the development of cardiotoxicity, and patients with cancer should be closely monitored during 5-FU chemotherapy.

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BACKGROUND: Fluoropyrimidines are chemotherapy drugs utilized to treat a variety of solid tumors. These drugs predominantly rely on the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, for their metabolism. Genetic mutations affecting this gene can cause DPYD deficiency, disrupting pyrimidine metabolism and increasing the risk of toxicity in cancer patients treated with 5-fluorouracil. The severity and type of toxic reactions are influenced by genetic and demographic factors and, in certain instances, can result in patient mortality. Among the more than 50 identified variants of DPYD, only a subset has clinical significance, leading to the production of enzymes that are either non-functional or impaired. The study aims to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency. METHODS: The meta-analysis selected and evaluated 9685 studies from Pubmed, Cochrane, Embase and Web of Science databases. Only studies examining the main DPYD variants (DPYD*2A, DPYD p.D949V, DPYD*13 and DPYD HapB3) were included. Statistical Analysis was performed using R, version 4.2.3. Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed with I2 statistics. RESULTS: There were 36 prospective and retrospective studies included, accounting for 16,005 patients. Most studies assessed colorectal cancer, representing 86.49% of patients. Other gastrointestinal cancers were evaluated by 11 studies, breast cancer by nine studies and head and neck cancers by five studies. Four DPYD variants were identified as predictors of severe fluoropyrimidines toxicity in literature review: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062) and DPYD Hap23 (rs56038477). All 36 studies assessed the DPYD*2A variant, while 20 assessed DPYD p.D949V, 7 assessed DPYD*13, and 9 assessed DPYDHap23. Among the 587 patients who tested positive for at least one DPYD variant, 13 died from fluoropyrimidine toxicity. Conversely, in the non-carrier group there were 14 treatment-related deaths. Carriers of DPYD variants was found to be significantly correlated with treatment-related mortality (OR = 34.86, 95% CI 13.96-87.05; p < 0.05). CONCLUSIONS: This study improves our comprehension of how the DPYD gene impacts cancer patients receiving fluoropyrimidine chemotherapy. Identifying mutations associated with dihydropyrimidine dehydrogenase deficiency may help predict the likelihood of serious side effects and fatalities. This knowledge can be applied to adjust medication doses before starting treatment, thus reducing the occurrence of these critical outcomes.

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Di-Hidrouracila Desidrogenase (NADP) , Fluoruracila , Neoplasias , Humanos , Di-Hidrouracila Desidrogenase (NADP)/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/mortalidade , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Farmacogenética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Deficiência da Di-Hidropirimidina Desidrogenase/induzido quimicamente

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PURPOSE: To investigate the visual prognosis of ocular surface squamous neoplasia (OSSN) after tumor resection and ocular surface reconstruction, and clarify factors that influence recurrence. STUDY DESIGN: Retrospective cohort study. METHODS: Medical records of all patients who underwent surgical treatment for OSSN at our hospital between January 1996 and December 2019 were reviewed. Tumor size/location, histological classification, surgical procedure, intraoperative mitomycin-C use, and postoperative topical 5-fluorouracil (5-FU) administration were examined, and pre and postoperative visual acuity (VA) were compared to elucidate factors that influence disease recurrence. RESULTS: Tumor excision was performed in 70 eyes of 70 cases (43 men, 27 women; average age: 71.6 ± 12.6 years) with dysplasia (8 eyes), carcinoma in situ (26 eyes), and invasive squamous cell carcinoma (36 eyes). Tumors were found in the limbus (N = 59 eyes), palpebral conjunctiva (N = 8 eyes), and from the bulbar to palpebral conjunctiva (N = 3 eyes). Surgical procedures performed were limbal transplantation/keratoepithelioplasty (N = 29 eyes), cultivated oral mucosal epithelial transplantation (N = 3 eyes), and auto-conjunctival epithelium transplantation (N = 2 eyes). Ocular surface was reconstructed using amniotic membrane, donor cornea, or cultivated epithelial sheet. The mean follow-up was 38.6 ± 38.6 months (range, 2 months to 13.8 years). VA postoperatively improved in 25 (61.0%) cases. Recurrence occurred in 19 (27.1%) cases at from 2 to 50 months (median: 12.5 months) postoperative. Uni- and multivariate analyses revealed that presurgical tumor size and postoperative administration of 5-FU were significantly related to recurrence. CONCLUSION: Combined surgical excision and postoperative topical 5-FU administration effectively prevented OSSN recurrence, and ocular surface reconstruction contributed to improvement of VA.

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5-Fluorouracil (5-FU) is frequently used to treat colorectal cancer (CRC), but its clinical application is limited by its toxicity. Natural compounds have been combined with chemotherapeutic drugs to reduce chemotherapy-related toxicity. Diosmetin, a natural flavonoid, has demonstrated anticancer effects against CRC. This study investigated diosmetin's potential in combination with 5-FU using a murine model of HCT-116 colon cancer xenografts in nu/nu nude mice. HCT-116 cells were injected into the right flanks of mice, and once tumors reached a size of 50 mm3, the mice were treated with diosmetin (100 mg/kg), 5-FU (30 mg/kg), or a combination of both at two dose levels (100 + 30 mg/kg and 50 + 15 mg/kg) for 4 weeks. Blood and tumors were collected on the final day for further analysis. Mice treated with the higher combination dose exhibited the smallest tumor volume (330.91 ± 88.49 mm3). Biochemistry and histology analysis showed no toxicity or abnormalities in the liver, kidney, and heart with the combination therapy. Immunohistochemistry results revealed a notable reduction in the proliferation marker (Ki67) and inflammation marker (TLR4) in tumors from high-dose combination-treated mice. Moreover, immunofluorescence data indicated increased levels of apoptotic markers (Bax, Caspase-3, p53, p21) and downregulation of anti-apoptotic protein (Bcl-2) in the high-dose combination group. The findings suggest that 100 mg/kg of diosmetin combined with 30 mg/kg 5-FU significantly reduced tumor volume and had a less toxic effect on the heart compared to 5-FU monotherapy.

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We have shown the induction of CD11b+Ly6C+ monocytic myeloid-derived suppressor cells (M-MDSCs) during infection of B6 mice by LP-BM5 immunodeficiency-inducing retrovirus. We published that the molecular mechanisms of these M-MDSCs vary, and depend on the cell type targeted by the suppression -defined by use of biochemical inhibitors, mouse M-MDSCs knock-out strains and blocking antibodies. These M-MDSCs suppressed proliferation and function of T cells, via nitric oxide synthase/nitric oxide; and that of B cells, ∼50% via INOS/NO along with the negative checkpoint regulator VISTA, reactive nitrogen and oxygen species, and other soluble mediators. Here, LP-BM5 infected mice were treated weekly with 5-Fluorouracil (5-FU), resulting in depletion of peripheral blood and splenic M-MDSCs, reduced MDSC activity, and significantly decreased standard disease parameters of: splenomegaly, impaired B-and T-cell ex vivo polyclonal responses, and viral load. In addition, 5-FU treatment significantly increased percentages of CD4+ and CD8+ T cells.

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Emerging chemical contaminants (ECCs) are among the major environmental threats in present century. A variety of ECCs is released into aquatic environments with little knowledge about their long-term impacts to organisms. We examined the role of acclimation of the freshwater rotifer Brachionus calyciflorus to silver nanoparticles (Ag-NPs) and 5-fluorouracil (5-FU) for determining their ability to deal with these ECCs individually and in mixtures along multiple generations. Additionally, transgenerational effects were also assessed during the recovery phase. Rotifers acclimated at EC10 of Ag-NPs along generations showed a higher ability to deal with higher concentrations of these nanoparticles or 5-FU along generations. Rotifers acclimated to EC10 of 5-FU showed varied responses, as their population growth rates were affected at the initial generations once exposed to higher concentration (EC50) of the same or a new contaminant; however, the rotifers acquired resistance in later generations. The exposure of generational Ag-NP-acclimated rotifers to the mixture of Ag-NPs and 5-FU at EC50 led to a shift from no effects to negative effects along successive generations, suggesting a decrease in resistance, which remained even in the post-exposure recovery phase. Similar transgenerational adverse effects were also observed for the generational Ag-NP-acclimated rotifers released from 5-FU. Rotifers acclimated to 5-FU showed a decrease in population growth rate at the first generation of recovery phase, possibly shifting their optimal environmental conditions when released from contaminants. Overall, our results suggest that rotifers had a high level of plasticity to ECC exposure in freshwaters; however, acclimation can be generic or contaminant dependent.

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5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-ß-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1ß, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.

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Senescência Celular , Fluoruracila , Células Endoteliais da Veia Umbilical Humana , Inflamação , Ácido Oleanólico , Ácido Oleanólico/farmacologia , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Humanos , Senescência Celular/efeitos dos fármacos , Animais , Camundongos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos BALB C , Intestinos/efeitos dos fármacos , Intestinos/patologia , Masculino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia

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Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer-related mortality worldwide. The efficacy of chemotherapy agents in CRC treatment is often limited due to toxic side effects, heterogeneity of cancer cells, and the possibility of chemoresistance which promotes cancer cell survival through several mechanisms. Combining chemotherapy agents with natural compounds like curcumin, a polyphenol compound from the Curcuma longa plant, has been reported to overcome chemoresistance and increase the sensitivity of cancer cells to chemotherapeutics. Curcumin, alone or in combination with chemotherapy agents, has been demonstrated to prevent chemoresistance by modulating various signaling pathways, reducing the expression of drug resistance-related genes. The purpose of this article is to provide a comprehensive update on studies that have investigated the ability of curcumin to enhance the efficacy of chemotherapy agents used in CRC. It is hoped that it can serve as a template for future research on the efficacy of curcumin, or other natural compounds, combined with chemotherapy agents to maximize the effectiveness of therapy and reduce the side effects that occur in CRC or other cancers.

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The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens demands urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. Herein, we identified the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimal inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited the potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-ß-lactamases (MBLs), such as NDM and IMP, or serine ß-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., with 32 of them obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcriptional and expressional level of the blaNDM-5 gene. Additionally, the 5-FU combined with meropenem can enhance bacterial metabolism, and stimulate the production of Reactive Oxygen Species (ROS), thereby rendering bacteria more susceptible to meropenem. This drug combination could effectively elevate the survival rate from 16.7% to 83.3% compared to meropenem monotherapy, and reduce bacteria loads in tissues in a mouse systemic infection model. Collectively, these findings reveal that the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against carbapenem-resistant bacteria infections.

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The increasing use of hyaluronic acid (HA) implants has made adverse effects more apparent. Here, we present a rare case of massive allergic dermatitis due to HA injections. We performed dermoscopy and color ultrasound, which clarified that this was an allergic dermatitis caused by fillers, and analyzed the possible causes of the allergy. Common treatments were compared, and the advantages of 5-FU-based treatment regimens and their associated mechanisms were noted. A low dose of 5-fluorouracil and triamcinolone acetonide was administered to the patient's entire face and neck, and significant efficacy was achieved. We aimed to gather evidence on extensive dermatitis caused by HA injection, provide new perspectives and solutions for subsequent HA injections, and promote further research on the potential mechanisms of extensive skin inflammation and allergies caused by local HA injections.

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Zinc-phosphate/hydroxyapatite hybrid form (ZP/HP) in core-shell nanostructure was developed and functionalized with both chitosan (CS@ZP/HP) and ß-cyclodextrin (CD@ZP/HP) as bio-composite of enhanced physicochemical and biological properties. These structures were assessed as potential deliveries of 5-fluorouracil, exhibiting enhanced loading, release, and anti-cancer behaviors. The functionalization strongly prompted the loading effectiveness to be 301.3 mg/g (CS@ZP/HP) and 342.8 mg/g (CD@ZP/HP) instead of 238.9 mg/g for ZP/HP. The loading activities were assessed based on the hypotheses of traditional kinetic and isotherm models, alongside the computational variables of the monolayer model with a single energetic site as an advanced isotherm model. The functionalized versions exhibit much greater loading efficacy compared to ZP/HP as a result of the increment in the density of the existing loading sites [Nm(5-Fu) = 78.85 mg/g (ZP/HP), 93.87 mg/g (CS@ZP/HP), and 117.8 mg/g (CD@ZP/HP)]. Furthermore, the loading energies of approximately 40 kJ/mol, together with the loading potential of each receptor (n > 1) and Gaussian energies of approximately 8 kJ/mol, indicate the physical entrapment of 5-Fu molecules according to a vertical orientation. The materials mentioned verify long-term and continuous release characteristics. Following the modification processes, this behavior became faster as both CS@ZP/HP and CD@ZP/HP displayed complete release within 120 h at pH 1.2. The kinetic studies and diffusing exponent (>0.45) indicate that release characteristics are controlled by both diffusion and erosion processes. These carriers also markedly increase the cytotoxicity of 5-Fu against HCT-116 colorectal cancer cell lines: 5-Fu-ZP/HP (3.2% cell viability), 5-Fu-CS@ZP/HP (1.12% cell viability), and 5-Fu-CD@ZP/HP (0.63% cell viability).

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Colon cancer is the third most common cancer worldwide, with high mortality. Adverse side effects and chemoresistance of the first-line chemotherapy 5-fluorouracil (5-FU) have promoted the widespread use of combination therapies. Thymoquinone (TQ) is a natural compound with potent antioxidant activity. Loading antioxidants into nano delivery systems has been a major advance in enhancing their bioavailability to improve clinical application. Hence, this study aimed to prepare the optimal TQ-loaded calcium carbonate nanoparticles (TQ-CaCO3 NPs) and investigate their therapeutic potential and underlying molecular mechanisms of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Firstly, we developed purely aragonite CaCO3 NPs with a facile mechanical ball-milling method. The pH-sensitive and biocompatible TQ-CaCO3 NPs with sustained release properties were prepared using the optimal synthesized method (a high-speed homogenizer). The in vitro study revealed that the combination of TQ-CaCO3 NPs (15 µM) and 5-FU (7.5 µM) inhibited CT26 cell proliferation and migration, induced cell apoptosis and cell cycle arrest in the G0/G1 phase, and suppressed the CT26 spheroid growth, exhibiting a synergistic effect. Finally, network pharmacology and molecular docking results indicated the potential targets and crucial signaling pathways of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Therefore, TQ-CaCO3 NPs combined with 5-FU could enhance the anti-colon cancer effects of 5-FU with broader therapeutic targets, warranting further application for colon cancer treatment.

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Although the risk of fluoropyrimidine toxicity may be decreased by identifying poor metabolizers with a preemptive dihydropyrimidine dehydrogenase (DPYD) test, following international standards, many patients with wild-type (WT) genotypes for classic variations may still exhibit adverse drug reactions (ADRs). Therefore, the safety of fluoropyrimidine therapy could be improved by identifying new DPYD polymorphisms associated with ADRs. This study was carried out to assess whether testing for the underestimated c.2194G>A (DPYD*6 polymorphism, rs1801160) is useful, in addition to other well-known variants, in reducing the risk of ADRs in patients undergoing chemotherapy treatment. This retrospective study included 132 patients treated with fluoropyrimidine-containing regimens who experienced ADRs such as gastrointestinal, dermatological, hematological, and neurological. All subjects were screened for DPYD variants DPYD2A (IVS14+1G>A, c.1905+1G>A, rs3918290), DPYD13 (c.1679T>G, rs55886062), c.2846A>T (rs67376798), c.1236G>A (rs56038477), and c.2194G>A by real-time polymerase chain reaction (RT-PCR). In this cohort, the heterozygous c.2194G>A variant was present in 26 patients, while 106 individuals were WT; both subgroups were compared for the incidence of ADRs. This assessment revealed a high incidence of gastrointestinal and hematological ADRs in DPYD6 carriers compared to WT. Moreover, we have shown a higher prevalence of ADRs in females compared to males when stratifying c.2194G>A carrier individuals. Considering that c.2194G>A was linked to clinically relevant ADRs, we suggest that this variant should also be assessed preventively to reduce the risk of fluoropyrimidine-related ADRs.

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5-Fluorouracil (5-FU) is widely used in chemotherapy but poses serious risks of cardiotoxicity, which can significantly affect treatment outcomes. Identifying interventions that can prevent these adverse effects without undermining anticancer efficacy is crucial. This study investigates the efficacy of Thymoquinone (TQ) and Hesperidin (HESP) in preventing cardiotoxicity induced by 5-FU in Wistar rats and elucidates the molecular interactions through docking studies. We employed an experimental design involving multiple groups of Wistar rats exposed to 5-FU, with and without the concurrent administration of TQ and HESP. Cardiac function markers, oxidative stress indicators, and inflammatory markers were assessed. Additionally, molecular docking was used to analyze the interaction of TQ and HESP with key inflammatory proteins. Treatment with TQ and HESP not only lowered levels of cardiac enzymes but also improved antioxidant capacity and reduced inflammation in cardiac tissues. Notably, the combination of TQ and HESP provided more significant protective effects than either agent alone. Molecular docking supported these findings, showing effective binding of TQ and HESP to inflammatory targets. TQ and HESP demonstrate potential as protective agents against cardiotoxicity in 5-FU-treated rats, with their combined use offering enhanced protection. These findings suggest a viable strategy for reducing cardiac risks associated with 5-FU chemotherapy.

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Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential ß-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/ß-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine.

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Neoplasias do Colo , Sinergismo Farmacológico , Fluoruracila , Taurina , Taurina/farmacologia , Animais , Fluoruracila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Ratos , Masculino , Modelos Animais de Doenças , Adenocarcinoma/tratamento farmacológico , 1,2-Dimetilidrazina , Ratos Wistar , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia

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PURPOSE: Co-administration of microRNAs and chemotherapy drugs effectively treats several cancers. The current study sought to investigate the function of matrix metalloproteinase 16 (MMP16) and miR-193a-5p in the pathogenesis of gastric cancer (GC). MATERIALS/METHODS: Sixty-five surgical patients, 15 receiving 5-fluorouracil (5-FU), provided GC and adjacent non-cancerous tissue. Following that, qPCR was used to assess the expression levels of MMP16 and miR-193a-5p in GC cells. The impact of miR-193a-5p and 5-FU administration on MMP16 mRNA expression was evaluated using qRT-PCR and Western blotting. MTT and Scratch tests were also conducted to assess their effects on cell viability and migration. Moreover, a rescue experiment using an MTT assay was performed. Using flow cytometry, the apoptotic rate was calculated. Finally, it was evaluated how MMP16 and miR-193a-5p related to the clinicopathological characteristics of the patients. RESULTS: The current study found that while MMP16 expression increased in GC patients (P<0.0001), miR-193a-5p expression significantly decreased (P<0.001). MMP16 down-regulation was another effect of miR-193a-5p replacement, particularly when 5-FU was added (P<0.01). In addition, this study found that miR-193a-5p, by concentrating on MMP16, decreased the migration of GC cells brought on by MMP16. In GC cell lines, miR-193 and 5-FU induce apoptosis, with the 5-FU being more pronounced when combined with mir-193, according to flow cytometry results. A strong correlation was also found between clinicopathological traits associated with MMP16 and miR-193a-5p. CONCLUSIONS: These findings suggest that miR-193a-5p, in conjunction with 5-FU, down-regulates MMP16 in GC, where it suppresses tumor growth.

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Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC-such as 5-fluorouracil (5FU)-remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.

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Background: L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV. Methods: Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU-mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). Results: l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT-transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. Conclusion: In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.

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14-3-3σ functions as an oncogene in colorectal cancer and is associated with therapy resistance. However, the mechanisms underlying these observations are not clear. The results in this report demonstrate that loss of 14-3-3σ in colorectal cancer cells leads to a decrease in tumor formation and increased sensitivity to chemotherapy. The increased sensitivity to chemotherapy is due to a decrease in the expression of UPR pathway genes in the absence of 14-3-3σ. 14-3-3σ promotes expression of the UPR pathway genes by binding to the transcription factor YY1 and preventing the nuclear localization of YY1. YY1, in the absence of 14-3-3σ, shows increased nuclear localization and binds to the promoter of the UPR pathway genes, resulting in decreased gene expression. Similarly, a YY1 mutant that cannot bind to 14-3-3σ also shows increased nuclear localization and is enriched on the promoter of the UPR pathway genes. Finally, inhibition of the UPR pathway with genetic or pharmacological approaches sensitizes colon cancer cells to chemotherapy. Our results identify a novel mechanism by which 14-3-3σ promotes tumor progression and therapy resistance in colorectal cancer by maintaining UPR gene expression.

RESUMO

BACKGROUND: Drug resistance in colorectal cancer (CRC) is modulated by multiple molecular factors, which can be ascertained through genetic investigation. Single nucleotide polymorphisms (SNPs) within key genes have the potential to impair the efficacy of chemotherapeutic agents such as 5-fluorouracil (5-FU). Therefore, the identification of SNPs linked to drug resistance can significantly contribute to the advancement of tailored therapeutic approaches and the enhancement of treatment outcomes in patients with CRC. MATERIAL AND METHOD: To identify dysregulated genes in 5-FU-based chemotherapy responder or non-responder CRC patients, a meta-analysis was performed. Next, the protein-protein interaction (PPI) network of the identified genes was analyzed using the STRING database. The most significant module was chosen for further analysis. In addition, a literature review was conducted to identify drug resistance-related genes. Enrichment analysis was conducted to validate the main module genes and the genes identified from the literature review. The associations between SNPs and drug resistance were investigated, and the consequences of missense variants were assessed using in silico tools. RESULT: The meta-analysis identified 796 dysregulated genes. Then, to conduct PPI analysis and enrichment analysis, we were able to discover 23 genes that are intricately involved in the cell cycle pathway. Consequently, these 23 genes were chosen for SNP analysis. By using the dbSNP database and ANNOVAR, we successfully detected and labeled SNPs in these specific genes. Additionally, after careful exclusion of SNPs with allele frequencies below 0.01, we evaluated 6 SNPs from the HDAC1, MCM2, CDK1, BUB1B, CDC14B, and CCNE1 genes using 8 bioinformatics tools. Therefore, these SNPs were identified as potentially harmful by multiple computational tools. Specifically, rs199958833 in CDK1 (Val124Gly) was predicted to be damaging by all tools used. Our analysis strongly indicates that this specific SNP could negatively affect the stability and functionality of the CDK1 protein. CONCLUSION: Based on our current understanding, the evaluation of CDK1 polymorphisms in the context of drug resistance in CRC has yet to be undertaken. In this investigation, we showed that rs199958833 variant in the CDK1 gene may favor resistance to 5-FU-based chemotherapy. However, these findings need validation in an independent cohort of patients.