Thymoquinone Increases the Sensitivity of SW-480 Colon Cancer Cells to 5-Fluorouracil.

Background: Studies have concentrated on the therapeutic potential of thymoquinone (TQ), a natural polyphenol, in diverse malignancies, such as colorectal cancer. Nevertheless, the precise mechanisms of TQ-mediated anticancer properties are not yet fully elucidated. Objective: The present study has been designed to scrutinize the impact of TQ on 5-fluorouracil (5-FU)-mediated apoptosis in SW-480 cells. Materials and Methods: SW-480 cells were treated with TQ, 5-FU, and a combination of TQ + 5-FU. MTT assay was employed to assess cell viability. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to evaluate apoptotic markers comprising Bcl-2, Bax, and caspase-9 expression levels. The γ-H2AX protein expression was assessed by western blotting, and Annexin V flow cytometry was implemented to determine the apoptosis rate. Results: 5-FU significantly reversed the cell proliferation in a dose-dependent circumstance. The concurrent administration of TQ and 5-FU led to a substantial inhibition of cell growth in comparison to single treatments (p < 0.05). TQ also facilitated apoptosis via upregulating Bax and caspase-9 proapoptotic markers and suppressing antiapoptotic mediators, like Bcl-2. In addition, TQ augmented 5-FU-induced apoptosis in SW-480 cells. 5-FU, combined with TQ, increased the protein expression of γ-H2AX in SW-480 cells compared with groups treated with TQ and 5-FU alone. Conclusion: The present study's findings unveil the significance of TQ as a potential therapeutic substance in colorectal cancer, particularly through enhancing 5-FU-induced apoptosis.

The function and mechanism of circRNAs in 5-fluorouracil resistance in tumors: Biological mechanisms and future potential.

5-Fluorouracil (5-FU) is a well-known chemotherapy drug extensively used in the treatment of breast cancer. It works by inhibiting cancer cell proliferation and inducing cell death through direct incorporation into DNA and RNA via thymidylate synthase (TS). Circular RNAs (circRNAs), a novel family of endogenous non-coding RNAs (ncRNAs) with limited protein-coding potential, contribute to 5-FU resistance. Their identification and targeting are crucial for enhancing chemosensitivity. CircRNAs can regulate tumor formation and invasion by adhering to microRNAs (miRNAs) and interacting with RNA-binding proteins, regulating transcription and translation. MiRNAs can influence enzymes responsible for 5-FU metabolism in cancer cells, affecting their sensitivity or resistance to the drug. In the context of 5-FU resistance, circRNAs can target miRNAs and regulate biological processes such as cell proliferation, cell death, glucose metabolism, hypoxia, epithelial-to-mesenchymal transition (EMT), and drug efflux. This review focuses on the function of circRNAs in 5-FU resistance, discussing the underlying molecular pathways and biological mechanisms. It also presents recent circRNA/miRNA-targeted cancer therapeutic strategies for future clinical application.

PEG-modified Fe2O3 coated agarose hydrogel: A synthesized nanocomposite for regulated 5-fluorouracil delivery.

An innovative pH-responsive nanocomposite, comprising agarose (AGA) modified with polyethylene glycol (PEG) hydrogel and coated with ferric oxide (Fe2O3), has been formulated to facilitate the precise administration of 5-fluorouracil (5-Fu) to breast cancer cells. By utilizing a double emulsion technique, the size of the nanocomposites was significantly reduced through the application of almond oil; the inclusion of span 80 further improved their uniformity. The physiochemical properties of the nanocomposite were thoroughly examined by Fourier Transformed Infrared (FT-IR), X-ray diffraction (XRD), Field Emission-Scanning Electron Microscope (FE-SEM), Vibrating Sample Magnetometer (VSM), dynamic light scattering (DLS), and zeta potential tests. The verification of the uniform particle distribution was achieved by employing FE-SEM and VSM analyses. The average diameter of the particles was 223 nm, and their zeta potential was -47.6 mV. In addition, the nanocomposite exhibited a regulated release of 5-Fu at pH 5.4 and pH 7.4, as indicated by an in vitro drug release profile. PEG-AGA- Fe2O3@5-Fu exhibited biocompatibility, as indicated by the lack of deleterious effects observed in tumor cells. This revolutionary nanocomposite demonstrates exceptional promise as a vehicle for breast cancer treatment, underscoring its significance as a significant progression in the ongoing pursuit of novel nanotechnologies for cancer therapy.

Adverse drug events associated with fluorouracil use in patients with metastatic colorectal cancer: a real-world pharmacovigilance study based on the FDA adverse event reporting system.

BACKGROUND: Fluorouracil (5-FU) is widely used to treat metastatic colorectal cancer (mCRC), but real-world safety data is limited. Our study aimed to evaluate 5-FU's safety profile in a large mCRC population using the FAERS database. RESEARCH DESIGN AND METHODS: We conducted disproportionality analyses to identify adverse drug events associated with 5-FU use in mCRC patients from 2004 to 2023. Subgroup analyses, gender difference analyses, and logistic regression were also performed. RESULTS: We identified 1,458 reports with 5-FU as the primary suspected drug, with males accounting for 48.8% of reports. Gastrointestinal disorders were the most common adverse event (864 cases), while pregnancy-related conditions showed the strongest signal intensity (ROR = 2.97). We found 19 preferred terms with positive signals, including ischemic hepatitis (ROR = 59.32), blood iron increased (ROR = 59.32), and stress cardiomyopathy (ROR = 51.94). Males were more susceptible to weight loss and skin toxicity. Most adverse events occurred within the first month of 5-FU administration. CONCLUSION: Our study provides a comprehensive analysis of 5-FU's safety profile in mCRC patients, helping healthcare professionals mitigate risks in clinical practice.

Innovative Strategies to Combat 5-Fluorouracil Resistance in Colorectal Cancer: The Role of Phytochemicals and Extracellular Vesicles.

Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being a major obstacle to effective treatment. Despite advancements, resistance to 5-FU remains formidable due to complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation of cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated resistance pathways. Traditional chemotherapy often results in high toxicity, highlighting the need for alternative approaches with better efficacy and safety. Phytochemicals (PCs) and EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, often exhibit lower toxicity and can target multiple pathways involved in cancer progression and drug resistance. EVs can facilitate targeted drug delivery, modulate the immune response, and interact with the TME to sensitize cancer cells to treatment. However, the potential of PCs and engineered EVs in overcoming 5-FU resistance and reshaping the immunosuppressive TME in CRC remains underexplored. Addressing this gap is crucial for identifying innovative therapies with enhanced efficacy and reduced toxicities. This review explores the multifaceted mechanisms of 5-FU resistance in CRC and evaluates the synergistic effects of combining PCs with 5-FU to improve treatment efficacy while minimizing adverse effects. Additionally, it investigates engineered EVs in overcoming 5-FU resistance by serving as drug delivery vehicles and modulating the TME. By synthesizing the current knowledge and addressing research gaps, this review enhances the academic understanding of 5-FU resistance in CRC, highlighting the potential of interdisciplinary approaches involving PCs and EVs for revolutionizing CRC therapy. Further research and clinical validation are essential for translating these findings into improved patient outcomes.

pH-responsive chitosan-mediated spherical mesoporous silica microspheres for high loading and controlled delivery of 5-Fluorouracil.

The objective of this study is to develop a drug carrier to overcome the inherent drawbacks of 5-Fluorouracil (5-Fu), including low bioavailability, short half-life, and systemic toxicity. In the present work, mesoporous silica nanoparticles (MSNs) capped by chitosan (CS) to encapsulate 5-Fu (5-Fu MSNs/CS) were fabricated by the sol-gel process, ultrasonic impregnation, and emulsion cross-linking. The 5-Fu MSNs/CS microspheres exhibit pH-responsive drug release and remarkable drug encapsulation capacity, as well as perfect sphericity, high specific surface area (680.62 cm2/g), and uniform particle size (2.64 ± 0.05 µm). The drug-loading content and encapsulation efficiency are 14.12 ± 0.53 % and 82.21 ± 2.13 %, respectively. The cumulative release of 5-Fu from MSNs/CS microspheres is fast and sustained at pH 5.0 (89.56 ± 0.97 %) compared to that at pH 7.4 (57.88 ± 0.91 %) in 96 h, and it is Fickian diffusion controlled. In conclusion, the MSNs/CS microspheres prepared in this study could be potential carriers for 5-Fu delivery.

Gentisic acid attenuates 5-fluorouracil-induced ovotoxicity in rats via modulating Nrf2 signalling: An experimental approach.

5-Fluorouracil (5-FU) is the third most used chemotherapeutic in the world with its anticancer effect resulting from its potential to block DNA replication. Like other cytotoxic agents, 5-FU has side effects on healthy tissues, and the reproductive system is among the tissues most affected by these undesirable effects. Gentisic acid (GEA) is a secondary metabolite that is abundant in fruits, vegetables and spices and has antioxidant activity. This study was conducted to investigate the toxicity of 5-FU in rat ovarian tissue and to determine the therapeutic activity of GEA on ovotoxicity caused by 5-FU. The results showed that 5-FU caused histopathological findings by suppressing Nrf2 pathway and accordingly increasing oxidative stress, inflammation, endoplasmic reticulum stress and apoptosis. However, GEA treatments after 5-FU application ameliorated 5-FU-induced ovotoxicity dose-dependently through activation of Nrf2 pathway. All these findings provided strong evidence supporting the hypothesis that GEA treatment may have therapeutic effects against 5-FU-induced ovarian damage. However, the beneficial effect of GEA use in eliminating ovarian damage in women after 5-FU chemotherapy should continue to be investigated with more detailed molecular studies.

Synthesis and Evaluation of Gelatin-Chitosan Biofilms Incorporating Zinc Oxide Nanoparticles and 5-Fluorouracil for Cancer Treatment.

In this study, a novel multifunctional biofilm was fabricated using a straightforward casting process. The biofilm comprised gelatin, chitosan, 5-fluorouracil (5-FU)-conjugated zinc oxide nanoparticles, and polyvinyl alcohol plasticized with glycerol. The 5-FU-conjugated nanoparticles were synthesized via a single-step co-precipitation process, offering a unique approach. Characterization confirmed successful drug conjugation, revealing bar-shaped nanoparticles with sizes ranging from 90 to 100 nm. Drug release kinetics followed the Korsmeyer-Peppas model, indicating controlled release behavior. Maximum swelling ratio studies of the gelatin-chitosan film showed pH-dependent characteristics, highlighting its versatility. Comprehensive analysis using SEM, FT-IR, Raman, and EDX spectra confirmed the presence of gelatin, chitosan, and 5-FU/ZnO nanoparticles within the biofilms. These biofilms exhibited non-cytotoxicity to human fibroblasts and significant anticancer activity against skin cancer cells, demonstrating their potential for biomedical applications. This versatility positions the 5-FU/ZnO-loaded sheets as promising candidates for localized topical patches in skin and oral cancer treatment, underscoring their practicality and adaptability for therapeutic applications.

Cytostatic Bacterial Metabolites Interfere with 5-Fluorouracil, Doxorubicin and Paclitaxel Efficiency in 4T1 Breast Cancer Cells.

The microbiome is capable of modulating the bioavailability of chemotherapy drugs, mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic effects on cancer cells. In this study, we addressed the question of whether a set of cytostatic bacterial metabolites (cadaverine, indolepropionic acid and indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil and paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range, and the effects on cell proliferation were assessed. There was no interference between gemcitabine, irinotecan, methotrexate or rucaparib and the bacterial metabolites. Nevertheless, cadaverine and indolepropionic acid modulated the Hill coefficient of the inhibitory curve of doxorubicin and 5-fluorouracil. Changes to the Hill coefficient implicate alterations to the kinetics of the binding of the chemotherapy agents to their targets. These effects have an unpredictable significance from the clinical or pharmacological perspective. Importantly, indolepropionic acid decreased the IC50 value of paclitaxel, which is a potentially advantageous combination.

Specific depletion of myeloid-derived suppressor cells by the chemotherapeutic agent 5-Fluorouracil enhances protective immune response in Paracoccidioidomycosis.

BACKGROUND: Paracoccidioidomycosis (PCM), a systemic mycosis in Latin America, is regulated by suppressive mechanisms mediated by tolerogenic plasmacytoid-dendritic-cells and regulatory T-cells. Our recent studies revealed that myeloid-derived suppressor cells (MDSCs), are important mediators in PCM. Their suppressive activity on Th1/Th17 immunity was shown to be mediated by inhibitory effect of IL-10, IDO-1 and PD-L1. Studies revealed the chemotherapeutic drug 5-Fluorouracil (5-FU) as a selective MDSC apoptosis-inducing agent, but its in vivo effect on infectious processes remains poorly investigated. METHODS: MDSCs and other leukocytes were evaluated in the lungs of 5-FU-treated mice after four, six, and eight weeks of P. brasiliensis infection. Disease severity and immunological response were evaluated in MDSCs-depleted. RESULTS: 5-FU treatment caused a significant reduction of pulmonary MDSCs and fungal loads. The specific depletion of MDSCs by 5-FU reduced all pulmonary CD4+ T-cell populations (Th1, Th2, Th17, and Treg) resulting in improved tissue pathology and increased survival rates. Importantly, this reduction was concomitant with increased frequencies of Th1/Th17 cells and the increased levels of Th1/Th2/Th17 cytokines in the lungs and liver of treated mice suggesting an early and efficient protective effect of these cells. Furthermore, the immuneprotection conferred by the specific depletion of MDSCs by 5FU treatment could be reversed by the adoptive transfer of MDSCs. CONCLUSIONS: 5-FU treatment depletes lung-MDSCs of P. brasiliensis-infected mice resulting in enhanced immunity. The protective effect of 5-FU treatment in pulmonary PCM suggests that the specific depletion of MDSCs can be viewed as a potential immunotherapeutic tool for PCM.

Efficacy and Safety of Corticosteroid in Combination with 5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Systematic Review and Meta-analysis.

BACKGROUND: Addressing hypertrophic scars and keloids poses a significant challenge in the realm of preventive and curative medicine. Combination corticosteroid with 5-fluorouracil (5-FU) is presumed to enhance the treatment of hypertrophic scars and keloids, although supportive evidence is lacking. This study is aimed at comparing the efficacy and safety profile of a combined corticosteroid and 5-FU regimen in treating hypertrophic scars and keloids. METHODS: A comprehensive search was conducted for pertinent studies across various databases, including Web of Science, PubMed, Google Scholar, Cochrane Library, and Medline. The calculation of weighted mean difference (WMD), risk ratios (RR), odds ratios (OR), and 95% confidence intervals (CIs) was executed. Additionally, the Cochrane Collaboration's Risk of Bias Tool was utilized to evaluate potential bias risks. RESULTS: A total of 15 studies were involved. The effectiveness based on patient self-assessment and the effectiveness based on observer assessment were significantly higher in the corticosteroid+5-FU group compared to those treated with control. A meta-analysis of scar height showed that the corticosteroid+5-FU group performed better than the control group (WMD = -0.38, 95% CI -0.58 to -0.18). There was no significant difference between the corticosteroid+5-FU group and the control group in improving scar vascularity, pliability and pigmentation. The result revealed that the corticosteroid+5-FU group of patients had less adverse effect of hypopigmentation, skin atrophy and telangiectasia than the control group. CONCLUSION: The combined use of corticosteroids and 5-FU appears to be a more effective strategy for the treatment and prevention of hypertrophic scars and keloids, as evidenced by greater improvements in scar height and overall effectiveness, coupled with a reduced incidence of side effects. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Neoadjuvant radiotherapy combined with fluorouracil-cisplatin plus cetuximab in operable, locally advanced esophageal carcinoma: Results of a phase I-II trial (FFCD-0505/PRODIGE-3).

Background: Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20-25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab. Methods: A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx. Results: The phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached. Conclusions: Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity. Trial registration: This trial was registered with EudraCT number 2006-004770-27.

Preparation of Microsponge Drug Delivery System (MSDDS) Followed by a Scale-Up Approach.

In 1987, Won invented the solid-phase porous microsphere (MS), which stores bioactive compounds in many interconnected voids. Spherical particles (5-300 µm), MS, may form clusters of smaller spheres, resulting in many benefits. The current investigation focussed on gel-encased formulation, which can be suitable for dermal usage. First, quasi-emulsion (w/o/w) solvent evaporation was used to prepare 5-fluorouracil (5 FU) MS particles. The final product was characterized (SEM shows porous structure, FTIR and DSC showed drug compatibility with excipients, and gel formulation is shear-thinning) and further scaled up using the 8-fold method. Furthermore, CCD (Central Composite Design) was implemented to obtain the optimized results. After optimizing the conditions, including the polymer (600 mg, ethyl cellulose (EC), eudragit RS 100 (ERS)), stirring speed (1197 rpm), and surfactant concentration (2% w/v), we achieved the following results: optimal yield (63%), mean particle size (152 µm), drug entrapment efficiency (76%), and cumulative drug release (74.24% within 8 h). These findings are promising for industrial applications and align with the objectives outlined in UN Sustainable Development Goals 3, 9, and 17, as well as the goals of the G20 initiative.

In vitro cytoprotective and in vivo anti-oral mucositis effects of melatonin and its derivatives.

According to our preliminary study, melatonin and its N-amide derivatives (N-(2-(1-4-bromobenzoyl-5-methoxy-1H-indol-3-yl)ethyl)acetamide (BBM) and 4-bromo-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide (EBM)) inhibited the marker of acute inflammation in tests in vitro and in vivo. The anti-inflammatory agent is intended for the prevention and treatment of chemotherapy-induced toxicity. In this study aimed to evaluate the effect of melatonin and its derivatives on mechanisms related to chemotherapy-induced oral mucositis by in vitro ROS and 5-FU-induced human keratinocyte cells as well as in vivo oral mucositis model. In in vitro H2O2-induced HaCaT cells, BBM had the highest level of protection (34.57%) at a concentration 50 µM, followed by EBM (26.41%), and melatonin (7.9%). BBM also protected cells against 5-FU-induced to 37.69-27.25% at 12.5-100 µM while EBM was 36.93-29.33% and melatonin was 22.5-11.39%. In in vivo 5-FU-induced oral mucositis in mice, melatonin, BBM, and EBM gel formulations protected tissue damage from 5-FU similar to the standard compound, benzydamine. Moreover, the weight of mice and food consumption recovered more quickly in the BBM group. These findings suggested that it was possible to develop BBM and EBM as new therapeutic agents for the treatment of oral mucositis.

The association between systemic immune-inflammation index and cardiotoxicity related to 5-Fluorouracil in colorectal cancer.

BACKGROUND AND AIMS: The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort. METHODS: The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted. RESULTS: Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 109/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98). CONCLUSION: Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.

Effects of hypoxia on the growth of gastric cancer and the chemotherapeutic efficacy of 5-fluorouracil. / 缺氧对胃癌细胞生长和5-氟尿嘧啶化学治疗效果的影响.

OBJECTIVES: Hypoxia is an important cause of chemotherapy resistance in gastric cancer. However, little is known about the growth of gastric cancer under purely hypoxia conditions. This study aims to study the effect of hypoxia on the growth patterns of gastric cancer cells and explore the response of gastric cancer cells to the chemotherapeutic drug 5-fluorouracil (5-FU) in a hypoxic environment. METHODS: Gastric cancer cells MKN45 were cultured under 1% oxygen hypoxia and conventional air conditions. An intervention group with the addition of the chemotherapeutic drug 5-FU was also established. The proliferation and apoptosis of gastric cancer cells under different oxygen conditions and intervention groups were detected using the cell counting kit-8 (CCK-8) method, JC-1 mitochondrial membrane potential assay, and Annexin-V/PI double staining method. Cell cycle changes were detected by flow cytometry, and mitochondrial changes were detected using electron microscopy. RESULTS: In the absence of 5-FU intervention, compared with the normoxia group, the hypoxia group showed higher rates of early and late apoptosis and higher cell death rates as indicated by the JC-1 mitochondrial membrane potential assay, Annexin-V/PI double staining, and CCK-8 results. Flow cytometry results showed that the cell cycle was arrested in the G0/G1 phase without progression. Electron microscopy revealed more severe mitochondrial destruction. However, with 5-FU intervention, the hypoxia group showed lower apoptosis rates, more cell cycle progression, and less mitochondrial destruction compared with the normoxia group. CONCLUSIONS: Hypoxic environments promote apoptosis and even death in gastric cancer cells, but hypoxia counteracts the efficacy of the chemotherapeutic drug 5-FU, which may contribute to 5-FU chemotherapy resistance.

Cinobufacini enhances the therapeutic response of 5-Fluorouracil against gastric cancer by targeting cancer stem cells via AKT/GSK-3ß/ß-catenin signaling axis.

BACKGROUND: Gastric cancer stem cells (GCSCs) play crucial role in the development, recurrence, and resistance of gastric cancer (GC). Cinobufacini, a traditional Chinese medicine, offers significant advantages in improving tumor therapy. However, pre-clinical investigation into the antitumor effect and mechanism of Cinobufacini on GC is still lacking. Additionally, it has not been reported whether Cinobufacini is related to cancer stem cells (CSCs). METHODS: The CCK-8, clone formation, EdU staining, transwell and wound healing experiments were performed to assess the cell toxicity of Cinobufacini and demonstrate the preventive effects of Cinobufacini on proliferation, invasion, and migration of GC cells. Elucidating the underlying mechanism of Cinobufacini in GC based on the transcriptome sequencing. Flow cytometry assays, sphere formation assays, subcutaneous xenograft model in nude mice, and immunofluorescent staining have been used to investigate whether the anti-GC effect of Cinobufacini is associated with GCSCs and enhancing therapeutic response to 5-Fluorouracil (5-FU). RESULTS: Cinobufacini exerts minimal impact on normal human gastric epithelium cell GES-1, while significantly suppressing the proliferation, invasion, and migration of GC cell lines. Additionally, Cinobufacini attenuates the stemness of GCSCs by disrupting the AKT/GSK-3ß/ß-catenin signaling cascade. Moreover, Cinobufacin enhances the anti-tumor effects of 5-FU against GCSCs by reducing in vitro sphere formation and inhibiting subcutaneous graft tumor growth in vivo. CONCLUSIONS: Cinobufacini enhances the therapeutic response of 5-FU against GC by targeting CSCs via AKT/GSK-3ß/ß-catenin signaling axis. Our findings offer a crucial insight into the molecular mechanism of Cinobufacini's anticancer activity in GC.

Advancing targeted combination chemotherapy in triple negative breast cancer: nucleolin aptamer-mediated controlled drug release.

BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.

Rapid determination of uracil in biological fluids at mercury thin film electrode for early detection of potential 5-fluorouracil toxicity due to dihydropyrimidine dehydrogenase deficiency.

Determination of plasma uracil was reported as a method for evaluation of Dihydropyrimidine dehydrogenase (DPD) activity that is highly demanded to ensure the safe administration of 5-fluorouracil (5-FU)-based therapies to cancer patients. This work reports the development of a simple electroanalytical method based on adsorptive stripping square wave voltammetry (AdSWV) at mercury film-coated glassy carbon electrode (MF/GCE) for the highly sensitive determination of uracil in biological fluids that can be used for diagnosis of decreased DPD activity. Due to the formation of the HgII-Uracil complex at the electrode surface, the accuracy of the measurement was not affected by the complicated matrices in biological fluids including human serum, plasma, and urine. The high sensitivity of the developed method results in a low limit of detection (≈1.3 nM) in human plasma samples, falling below the practical cut-off level of 15 ng mL-1 (≈0.14 µM). This threshold concentration is crucial for predicting 5-FU toxicity, as reported in buffer, and ≤1.15% in biological samples), and accuracy (recovery percentage close to 100%).