RARE DISEASE
5-fluorouracil poisoning
5-fluorouracil poisoning
5-fluorouracil poisoning
Synonyms: 5-fluorouracil intoxication
Synonyms: 5-fluorouracil intoxication
Synonyms: 5-fluorouracil intoxication
Drug discovery
4
drugs
With orphan designations
Overview
5-fluorouracil poisoning results from overdose or prolonged low-dose administration of the chemotherapeutic agent, causing life-threatening gastrointestinal (nausea, vomiting, diarrhea) and hematologic (myelosuppression) toxicities, mucositis, and neuro/cardiotoxicity. Rapid recognition is critical, as uridine triacetate—the FDA-approved antidote—must be administered within 96 hours post-exposure to reverse toxicity [1][2][5][12].
Therapies
Uridine triacetate: Reduces mortality from 10% (supportive care) to 96% survival when given ≤96 hours post-overdose [2][5][12].
Supportive care: IV hydration, filgrastim for neutropenia, electrolyte repletion, and infection prevention [3][9].
Guidelines: Therapeutic drug monitoring (TDM) and pre-treatment DPYD genetic testing to mitigate toxicity risk [7][13].
Categories: rare disorders due to toxic effects
Research Papers
138 drug discovery papers about 5-fluorouracil poisoning. Recent publications:
138 drug discovery papers about 5-fluorouracil poisoning. Recent publications:
categories:
Small molecules
small molecules
2026-05-13 | Amelioration of 5-Fluorouracil-Induced Hepatorenal Toxicity by Epigallocatechin Gallate-Functionalized Selenium Nanoparticles: A Multi-Targeted Protective Approach.
5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent that is extensively utilized in the management of malignancies; however, its clinical utility is constrained by its narrow therapeutic index and dose-limiting toxicities. The study aimed to study the hepato-nephroprotective effects of epigallocatechin gallate (EGCG) and EGCG mediated selenium nanoparticles and their effect in mitigating the toxicity induced by 5-FU. EGCG-functionalized selenium nanoparticles (EGCG-SeNPs) were produced by mixing sodium selenite, with EGCG acting as both the reducing and stabilizing agent. Nanoparticles were characterized using UV-vis spectroscopy, FT-IR, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. 35 adult rats were randomly assigned to control, 5-FU, 5-FU + Na2SeO3, 5-FU + EGCG, and 5-FU + EGCG-SeNPs groups. Hepatorenal toxicity was induced by intraperitoneal 5-FU administration during the final five days of the experiment. Serum biochemical markers, tissue oxidative stress, antioxidant enzyme, inflammatory cytokine levels, and apoptosis-related gene expression were evaluated. Immunohistochemical analysis of Nrf2 and Keap1 and histopathological examination of tissues were performed. 5-FU induced severe hepatorenal toxicity, evidenced by marked elevations in liver and kidney function biomarkers, excessive oxidative stress, inflammatory cytokine overproduction, NF-κB activation, and apoptotic signaling. Treatment with EGCG-SeNPs markedly ameliorated 5-FU-induced hepatic and renal dysfunction, restoring liver enzyme and kidney biomarker levels to near-normal levels more effectively than EGCG or sodium selenite alone. EGCG-SeNPs significantly suppressed lipid peroxidation, NGAL, and inflammatory mediators while robustly enhancing antioxidant defenses and activating the Nrf2/HO-1 pathway with concomitant Keap-1 downregulation, strongly inhibited NF-κB signaling, normalized cytokine balance, reduced poly (ADP-ribose) (PAR) activation, and attenuated apoptosis. EGCG-SeNPs confer superior protection against 5-FU-induced hepatorenal toxicity compared to EGCG or inorganic selenium alone. The potent protective effects of EGCG-SeNPs are mediated through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, primarily via activation of the Nrf2/HO-1 axis and suppression of NF-κB signaling.
2026-02-14 | Ethyl gallate attenuates 5-fluorouracil induced hepatic injury via MAPK/NF-κB downregulation in rats.
5-Fluorouracil (5-FU) is known to cause liver injury in cancer patients. Experimental studies have reported that administration of 5-FU induces oxidative stress and inflammation in liver tissue. Ethyl gallate (EG), a plant-derived phytocompound, has been shown to possess antioxidant and anti-inflammatory properties. Therefore, in this study, we evaluated the protective effect of EG against 5-FU-induced acute liver injury in rats. Rats were intraperitoneally injected with a single dose of 5-FU (150 mg/kg) to induce acute liver injury. In separate groups, rats were concurrently treated with EG (10 and 20 mg/kg) or silymarin (SIL) daily once for 7 days. At the end of an experimental period, serum transaminase activities, oxidative stress markers, inflammatory markers, and histopathological changes were assessed in liver tissue. A single dose of 5-FU caused a significant increase of transaminases in serum and oxidative stress, and DNA fragmentation in liver tissue. 5-FU administration also decreased the mRNA expression of its catabolizing enzyme, dihydropyrimidine dehydrogenase. At the molecular level, 5-FU upregulated apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase 1, and extracellular signal-regulated kinase 1 mRNA expressions in liver tissue. It also downregulated nuclear factor erythroid 2-related factor 2 and upregulated its inhibitor Kelch-like ECH-associated protein 1, indicating oxidative stress. Similarly, 5-FU administration increased tumor necrosis factor-α and nuclear factor kappa B (NF-κB) expression while reducing its inhibitor, inhibitor of κB, confirming the activation of inflammation cascade. These abnormalities were significantly prevented in rats treated concurrently with EG or SIL. Histopathological analysis revealed reduced necrosis and better preservation of liver architecture in the 5-FU + EG and 5-FU + SIL groups. Our study demonstrates that EG and SIL treatments effectively alleviate 5-FU-induced acute liver injury by modulating 5-FU catabolism and suppressing the mitogen-activated protein kinase and NF-κB signaling pathways in rats.
2025-10-16 | Coenzyme Q10 Ameliorates Chemotherapy-Induced Neurotoxicity in iPSC-Derived Neurons by Reducing Oxidative Stress.
Chemotherapy-induced neurotoxicity (CIN) is a major barrier against optimal anticancer treatment. This study investigated the neuroprotective effects of the naturally occurring antioxidant, Coenzyme Q10 (CoQ10), against CIN using a model of induced pluripotent stem cell (iPSC)-derived neurons. iPSCs have consistently proven to be reliable for disease modeling and drug discovery. We employed cell viability, oxidative stress, and mitochondrial function assays to measure the effect of 10 μM CoQ10 on iPSC-derived motor neuron progenitors (iPSC-MNPs) that were exposed to five chemotherapeutic agents: 5-Fluorouracil, methotrexate, paclitaxel (0, 1, and 10 μM) and doxorubicin, and vincristine (0, 0.1, and 1 μM). Our findings show that CoQ10 significantly reversed the reduction in cell viability inflicted by the exposure of iPSCs-MNPs to all five chemotherapeutics. Moreover, CoQ10 treatment resulted in a marked reduction in intracellular ROS levels and enhancement of mitochondrial membrane potential (MMP) in a drug- and dose-dependent manners, highlighting its role in preserving mitochondrial health. This study is the first to explore the protective effects of CoQ10 against CIN using an iPSC-derived neuronal platform, offering insights into its potential therapeutic use. Further investigation is essential to validate these findings and to determine the behavioral effects of CoQ10 in in vivo models of CIN.
2025-08-25 | Nifuroxazide attenuated 5-fluorouracil-induced cardiac intoxication by regulating NLRP3/STAT-3, PPAR-γ, and apoptosis signals.
IntroductionFor many years, 5-fluorouracil (5-FU) has been utilized as a chemotherapeutic treatment for a variety of malignancies. Unfortunately, 5-FU causes cardiotoxicity, which restricts its clinical use. Nifuroxazide (NFX) is a STAT-3 inhibitor with antioxidant and anti-inflammatory effects.MethodsCardiotoxicity was induced by 5-FU (30 mg/kg) once daily for 5 days. NFX was administered in two doses, 25 and 50 mg.ResultsCompared to 5-FU-control rats, NFX significantly attenuates cardiotoxicity induced by 5-FU, as indicated by decreasing creatine kinase (CK)-MB, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) serum levels. Histopathological examinations confirmed the protective effects of NFX against histological abrasions induced by 5-FU. NFX attenuated the oxidative damage induced by 5-FU mediated by peroxisome proliferator-activated receptor gamma (PPAR-γ) signal activation. Moreover, NFX mitigated 5-FU-induced inflammation by suppressing nucleotide-binding domain, leucine-rich repeat-containing protein 3/signal transducer and activator of transcription 3 (NLRP3/STAT3) signal activation. Notably, these protective effects are dose-dependent. Additionally, NFX mitigated 5-FU-induced apoptosis by downregulating Bax, while upregulating Bcl-2.ConclusionsCollectively, NFX attenuated 5-FU-induced cardiac intoxication by regulating NLRP3/STAT-3, PPAR-γ, and Bax/Bcl-2 signals.
2025-08-23 | CF10 Displayed Improved Activity Relative to 5-FU in a Mouse CRLM Model Under Conditions of Physiological Folate
Background/Objective: At least 25% of colorectal cancer (CRC) patients develop liver metastases (CRLM), and chemotherapeutic regimens based on the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) provide a survival advantage, but long-term survival is uncommon. The primary molecular target of FP drugs is thymidylate synthase (TS). Methods: A TS/Top1 dual-targeting cytotoxic mechanism for CF10/LV was confirmed by TS ternary complex detection by Western blot and by immunofluorescence detection of Top1 cleavage complexes. CF10/LV activated the ATR/Chk1 pathway consistent with enhanced replication stress and induced apoptosis. In vivo studies showed CF10 and CF10/LV eradicated liver metastasis in a CRLM model without scarring or weight loss, displaying therapeutic advantages relative to legacy FPs. Results: We demonstrated that a nanoscale FP polymer, CF10, displayed greater potency than expected based on FP content in part through more direct conversion to the TS-inhibitory metabolite, FdUMP. In this study, we tested CF10 for potency advantages relative to 5-FU and trifluorothymidine (TFT, the FP component of TAS-102) and confirmed a general potency advantage for CF10 in CRC cell lines in the Broad Institute PRISM screen. We demonstrated that this potency advantage is retained in CRC cells cultured with human-like folate levels and is enhanced by LV co-treatment to a similar extent as that by 5-FU. Our results confirm CF10 development proceeding as a CF10/LV combination. Mechanistically, CF10 cytotoxicity closely correlates with poisons of DNA topoisomerase 1 (Top1) in the PRISM screen relative to 5-FU and TFT. Conclusions: Our pre-clinical data support an early-phase clinical trial for CF10 for treating liver-metastatic CRC.
proteins
2025-07-04 | Exploring novel protective role of semaglutide in 5-fluorouracil-induced hepatotoxicity: Insights into phosphorylated CREB, PINK1/Parkin-mediated mitophagy, and NF-κB/NLRP3 pathways.
Semaglutide (Sema), a potent glucagon-like peptide-1 receptor agonist, is widely used in the management of type 2 diabetes mellitus due to its glucose-lowering effects. Beyond this, Sema also exhibits antioxidative, anti-inflammatory, antiapoptotic, and autophagy-enhancing properties. However, its potential role against 5-fluorouracil (5-FU)-induced hepatic injury has not yet been investigated. Hence, our study aims to investigate the hepatoprotective role of Sema against 5-FU-induced hepatotoxicity. Rats were randomly distributed in 5 groups: group I was the control group (saline only); group II and the rest of the groups except the normal group received 5-FU (150 mg/kg i.p.) to induce hepatotoxicity; group III received Sema (0.3 mg/kg orally) + 5-FU; group IV received Sema + 5-FU + chloroquine (CQ; 10 mg/kg i.p., 10 minutes prior to 5-FU);group V received 5-FU + CQ. Our results showed that 5-FU markedly increased hepatic enzyme levels, oxidative stress, inflammatory markers, and histological injury. However, pretreatment with Sema effectively counteracted these harmful effects by suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and enhancing PINK1/Parkin-mediated mitophagy. Notably, the addition of CQ, an autophagy inhibitor, abolished the protective role of Sema in autophagic flux. Furthermore, Sema reduced proinflammatory cytokines (tumor necrosis factor-α and interleukin-6), oxidative stress markers (malondialdehyde), and apoptotic markers (caspase-3), enhanced the antioxidant activity (glutathione), and promoted the activation of the phosphorylated CREB/Nrf2/HO-1 signaling pathway. In conclusion, Sema attenuates the 5-FU-induced liver injury through a multifaceted mechanism involving suppression of inflammation, oxidative stress, and apoptosis, as well as by increasing autophagic flux by inducing the phosphorylated CREB/PINK/Parkin trajectory pathway. These findings suggest that Sema holds promise as a novel therapeutic approach for preventing chemotherapy-induced liver toxicity. SIGNIFICANCE STATEMENT: Semaglutide, a GLP-1 receptor agonist, significantly mitigates 5-fluorouracil-induced hepatotoxicity in rats, suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and reducing oxidative stress and inflammation. Semaglutide also enhances mitophagy by activating the phosphorylated CREB/PINK1/Parkin pathway, aiding in the clearance of damaged mitochondria, confirmed using chloroquine, an autophagy inhibitor.
2024-08-08 | Trim47 prevents hematopoietic stem cell exhaustion during stress by regulating MAVS-mediated innate immune pathway.
The maintenance of hematopoietic stem cell (HSC) functional integrity is essential for effective hematopoietic regeneration when suffering from injuries. Studies have shown that the innate immune pathways play crucial roles in the stress response of HSCs, whereas how to precisely modulate these pathways is not well characterized. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 47 (Trim47) as a negative regulator of the mitochondrial antiviral-signaling protein (MAVS)-mediated innate immune pathway in HSCs. We find that Trim47 is predominantly enriched in HSCs, and its deficiency impairs the function and survival of HSCs after exposure to 5-flurouracil (5-FU) and irradiation (IR). Mechanistically, Trim47 impedes the excessive activation of the innate immune signaling and inflammatory response via K48-linked ubiquitination and degradation of MAVS. Collectively, our findings demonstrate a role of Trim47 in preventing stress-induced hematopoietic failure and thus provide a promising avenue for treatment of related diseases in the clinic.
2022-05-25 | Inflammatory cancer associated fibroblasts decisive role in therapy resistance among rectal cancer patients
Standard cancer therapy research targets tumor cells while not considering the damage on the tumor microenvironment (TME) and its associated implications in impairing therapy response. Employing patients-derived organoids (PDOs) and matched stroma cells or a novel murine preclinical rectal cancer model of local radiotherapy, it was demonstrated that tumor cells-derived IL-1α polarizes cancer-associated fibroblasts towards an inflammatory (iCAFs) phenotype. While numerous studies in different tumor entities highlighted the molecular heterogeneity of CAFs, so far there are no clear findings on their functional heterogeneity and relevance in therapy resistance and response. The present study molecularly characterized iCAFs subpopulation among RCA patients as well as the preclinical mouse model and importantly unraveled the detailed molecular mechanism underlying their contribution to impair therapy response. Mechanistically, iCAFs were demonstrated to be characterized by an upregulation of nitric oxide synthase (iNOS) which triggered accumulation of reactive nitrogen species (RNS) and subsequently an oxidative DNA damage response (DDR). Such a baseline IL-1α-driven DNA damage further sensitized iCAFs to a p53-mediated therapy induced senescence (TIS) causing extensive extracellular matrix (ECM) changes and induction of senescence associated secretory phenotype (SASP) that favored tumor progression and hindered tumor cell death. Moreover, iCAFs reversibility and repolarization into more quiescent like phenotype was demonstrated upon IL-1 signaling inhibition by anakinra, a recombinant IL-1 receptor antagonist (IL1RA). Accordingly, treating mice with anakinra or specific deletion of Il1r1 in CAFs sensitized stroma-rich resistant tumors to chemoradiotherapy (CRT). Similarly, targeting CAFs senescence by senotherapy (venetoclax chemical) or employing Trp53 deficient mice reverted therapy resistance among non-responsive tumors in vivo by reducing ECM deposition and consequently favoring CD8+ T cells intratumoral infiltration posttherapy. Importantly, rectal cancer patients that do not completely respond to neoadjuvant therapy displayed an iCAFs senescence program post-CRT. Moreover, these patients presented a baseline increased CAFs content, a dominant iCAFs signature that correlated with poorer disease-free survival (DFS) and a significantly reduced circulating IL1RA serum levels. While reduced pretherapeutic IL1RN gene expression predicted poor prognosis among RCA patients, IL1RA serum levels were associated with rs4251961 (T/C) single nucleotide polymorphism (SNP) in the IL1RN gene. Finally, functional validation assays revealed that conditioned media of PDOs drove inflammatory polarization of fibroblasts and consequently rendered them sensitive to RNS-mediated DNA damage and TIS. Collectively, the study highlighted a crucial and novel role of a CAFs subset, iCAFs, in therapy resistance among RCA patients, shedding light on their functional relevance by identifying IL-1 signaling as an appealing target for their repolarization and successful targeting. Therefore, it makes sense to combine the newly demonstrated and thoroughly proven therapeutic approach of targeting IL-1 signaling in combination with conventional CRT and possibly immunotherapy. This might have a major impact on RCA therapy and be of immense relevance for other stroma-rich tumors.
2017-08-22 | P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate synthase (TS) targeting
Abstract Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico /chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Consequently, decrease in Histone H3K9AC and increase in H3K27me3 marks at the DPYD promoter are observed concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition and DPYD repression by p53 is dependent on DNA-dependent protein kinase (DNA-PK) and Ataxia telangiectasia mutated (ATM) signaling. In-vivo , liver specific Tp53 loss increases the conversion of 5-FU to 5-FUH 2 in plasma and elicits a diminished 5-FU therapeutic response in a syngeneic colorectal tumor model consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through repression of DPYD expression, following metabolic stress imposed by nucleotide imbalance. These findings have implications for the toxicity and efficacy of the cancer therapeutic 5-FU.
2015-06-17 | Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma
Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific α-fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC.
small molecules
2026-05-13 | Amelioration of 5-Fluorouracil-Induced Hepatorenal Toxicity by Epigallocatechin Gallate-Functionalized Selenium Nanoparticles: A Multi-Targeted Protective Approach.
5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent that is extensively utilized in the management of malignancies; however, its clinical utility is constrained by its narrow therapeutic index and dose-limiting toxicities. The study aimed to study the hepato-nephroprotective effects of epigallocatechin gallate (EGCG) and EGCG mediated selenium nanoparticles and their effect in mitigating the toxicity induced by 5-FU. EGCG-functionalized selenium nanoparticles (EGCG-SeNPs) were produced by mixing sodium selenite, with EGCG acting as both the reducing and stabilizing agent. Nanoparticles were characterized using UV-vis spectroscopy, FT-IR, dynamic light scattering, zeta potential analysis, and transmission electron microscopy. 35 adult rats were randomly assigned to control, 5-FU, 5-FU + Na2SeO3, 5-FU + EGCG, and 5-FU + EGCG-SeNPs groups. Hepatorenal toxicity was induced by intraperitoneal 5-FU administration during the final five days of the experiment. Serum biochemical markers, tissue oxidative stress, antioxidant enzyme, inflammatory cytokine levels, and apoptosis-related gene expression were evaluated. Immunohistochemical analysis of Nrf2 and Keap1 and histopathological examination of tissues were performed. 5-FU induced severe hepatorenal toxicity, evidenced by marked elevations in liver and kidney function biomarkers, excessive oxidative stress, inflammatory cytokine overproduction, NF-κB activation, and apoptotic signaling. Treatment with EGCG-SeNPs markedly ameliorated 5-FU-induced hepatic and renal dysfunction, restoring liver enzyme and kidney biomarker levels to near-normal levels more effectively than EGCG or sodium selenite alone. EGCG-SeNPs significantly suppressed lipid peroxidation, NGAL, and inflammatory mediators while robustly enhancing antioxidant defenses and activating the Nrf2/HO-1 pathway with concomitant Keap-1 downregulation, strongly inhibited NF-κB signaling, normalized cytokine balance, reduced poly (ADP-ribose) (PAR) activation, and attenuated apoptosis. EGCG-SeNPs confer superior protection against 5-FU-induced hepatorenal toxicity compared to EGCG or inorganic selenium alone. The potent protective effects of EGCG-SeNPs are mediated through coordinated antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, primarily via activation of the Nrf2/HO-1 axis and suppression of NF-κB signaling.
2026-02-14 | Ethyl gallate attenuates 5-fluorouracil induced hepatic injury via MAPK/NF-κB downregulation in rats.
5-Fluorouracil (5-FU) is known to cause liver injury in cancer patients. Experimental studies have reported that administration of 5-FU induces oxidative stress and inflammation in liver tissue. Ethyl gallate (EG), a plant-derived phytocompound, has been shown to possess antioxidant and anti-inflammatory properties. Therefore, in this study, we evaluated the protective effect of EG against 5-FU-induced acute liver injury in rats. Rats were intraperitoneally injected with a single dose of 5-FU (150 mg/kg) to induce acute liver injury. In separate groups, rats were concurrently treated with EG (10 and 20 mg/kg) or silymarin (SIL) daily once for 7 days. At the end of an experimental period, serum transaminase activities, oxidative stress markers, inflammatory markers, and histopathological changes were assessed in liver tissue. A single dose of 5-FU caused a significant increase of transaminases in serum and oxidative stress, and DNA fragmentation in liver tissue. 5-FU administration also decreased the mRNA expression of its catabolizing enzyme, dihydropyrimidine dehydrogenase. At the molecular level, 5-FU upregulated apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase 1, and extracellular signal-regulated kinase 1 mRNA expressions in liver tissue. It also downregulated nuclear factor erythroid 2-related factor 2 and upregulated its inhibitor Kelch-like ECH-associated protein 1, indicating oxidative stress. Similarly, 5-FU administration increased tumor necrosis factor-α and nuclear factor kappa B (NF-κB) expression while reducing its inhibitor, inhibitor of κB, confirming the activation of inflammation cascade. These abnormalities were significantly prevented in rats treated concurrently with EG or SIL. Histopathological analysis revealed reduced necrosis and better preservation of liver architecture in the 5-FU + EG and 5-FU + SIL groups. Our study demonstrates that EG and SIL treatments effectively alleviate 5-FU-induced acute liver injury by modulating 5-FU catabolism and suppressing the mitogen-activated protein kinase and NF-κB signaling pathways in rats.
2025-10-16 | Coenzyme Q10 Ameliorates Chemotherapy-Induced Neurotoxicity in iPSC-Derived Neurons by Reducing Oxidative Stress.
Chemotherapy-induced neurotoxicity (CIN) is a major barrier against optimal anticancer treatment. This study investigated the neuroprotective effects of the naturally occurring antioxidant, Coenzyme Q10 (CoQ10), against CIN using a model of induced pluripotent stem cell (iPSC)-derived neurons. iPSCs have consistently proven to be reliable for disease modeling and drug discovery. We employed cell viability, oxidative stress, and mitochondrial function assays to measure the effect of 10 μM CoQ10 on iPSC-derived motor neuron progenitors (iPSC-MNPs) that were exposed to five chemotherapeutic agents: 5-Fluorouracil, methotrexate, paclitaxel (0, 1, and 10 μM) and doxorubicin, and vincristine (0, 0.1, and 1 μM). Our findings show that CoQ10 significantly reversed the reduction in cell viability inflicted by the exposure of iPSCs-MNPs to all five chemotherapeutics. Moreover, CoQ10 treatment resulted in a marked reduction in intracellular ROS levels and enhancement of mitochondrial membrane potential (MMP) in a drug- and dose-dependent manners, highlighting its role in preserving mitochondrial health. This study is the first to explore the protective effects of CoQ10 against CIN using an iPSC-derived neuronal platform, offering insights into its potential therapeutic use. Further investigation is essential to validate these findings and to determine the behavioral effects of CoQ10 in in vivo models of CIN.
2025-08-25 | Nifuroxazide attenuated 5-fluorouracil-induced cardiac intoxication by regulating NLRP3/STAT-3, PPAR-γ, and apoptosis signals.
IntroductionFor many years, 5-fluorouracil (5-FU) has been utilized as a chemotherapeutic treatment for a variety of malignancies. Unfortunately, 5-FU causes cardiotoxicity, which restricts its clinical use. Nifuroxazide (NFX) is a STAT-3 inhibitor with antioxidant and anti-inflammatory effects.MethodsCardiotoxicity was induced by 5-FU (30 mg/kg) once daily for 5 days. NFX was administered in two doses, 25 and 50 mg.ResultsCompared to 5-FU-control rats, NFX significantly attenuates cardiotoxicity induced by 5-FU, as indicated by decreasing creatine kinase (CK)-MB, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) serum levels. Histopathological examinations confirmed the protective effects of NFX against histological abrasions induced by 5-FU. NFX attenuated the oxidative damage induced by 5-FU mediated by peroxisome proliferator-activated receptor gamma (PPAR-γ) signal activation. Moreover, NFX mitigated 5-FU-induced inflammation by suppressing nucleotide-binding domain, leucine-rich repeat-containing protein 3/signal transducer and activator of transcription 3 (NLRP3/STAT3) signal activation. Notably, these protective effects are dose-dependent. Additionally, NFX mitigated 5-FU-induced apoptosis by downregulating Bax, while upregulating Bcl-2.ConclusionsCollectively, NFX attenuated 5-FU-induced cardiac intoxication by regulating NLRP3/STAT-3, PPAR-γ, and Bax/Bcl-2 signals.
2025-08-23 | CF10 Displayed Improved Activity Relative to 5-FU in a Mouse CRLM Model Under Conditions of Physiological Folate
Background/Objective: At least 25% of colorectal cancer (CRC) patients develop liver metastases (CRLM), and chemotherapeutic regimens based on the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) provide a survival advantage, but long-term survival is uncommon. The primary molecular target of FP drugs is thymidylate synthase (TS). Methods: A TS/Top1 dual-targeting cytotoxic mechanism for CF10/LV was confirmed by TS ternary complex detection by Western blot and by immunofluorescence detection of Top1 cleavage complexes. CF10/LV activated the ATR/Chk1 pathway consistent with enhanced replication stress and induced apoptosis. In vivo studies showed CF10 and CF10/LV eradicated liver metastasis in a CRLM model without scarring or weight loss, displaying therapeutic advantages relative to legacy FPs. Results: We demonstrated that a nanoscale FP polymer, CF10, displayed greater potency than expected based on FP content in part through more direct conversion to the TS-inhibitory metabolite, FdUMP. In this study, we tested CF10 for potency advantages relative to 5-FU and trifluorothymidine (TFT, the FP component of TAS-102) and confirmed a general potency advantage for CF10 in CRC cell lines in the Broad Institute PRISM screen. We demonstrated that this potency advantage is retained in CRC cells cultured with human-like folate levels and is enhanced by LV co-treatment to a similar extent as that by 5-FU. Our results confirm CF10 development proceeding as a CF10/LV combination. Mechanistically, CF10 cytotoxicity closely correlates with poisons of DNA topoisomerase 1 (Top1) in the PRISM screen relative to 5-FU and TFT. Conclusions: Our pre-clinical data support an early-phase clinical trial for CF10 for treating liver-metastatic CRC.
proteins
2025-07-04 | Exploring novel protective role of semaglutide in 5-fluorouracil-induced hepatotoxicity: Insights into phosphorylated CREB, PINK1/Parkin-mediated mitophagy, and NF-κB/NLRP3 pathways.
Semaglutide (Sema), a potent glucagon-like peptide-1 receptor agonist, is widely used in the management of type 2 diabetes mellitus due to its glucose-lowering effects. Beyond this, Sema also exhibits antioxidative, anti-inflammatory, antiapoptotic, and autophagy-enhancing properties. However, its potential role against 5-fluorouracil (5-FU)-induced hepatic injury has not yet been investigated. Hence, our study aims to investigate the hepatoprotective role of Sema against 5-FU-induced hepatotoxicity. Rats were randomly distributed in 5 groups: group I was the control group (saline only); group II and the rest of the groups except the normal group received 5-FU (150 mg/kg i.p.) to induce hepatotoxicity; group III received Sema (0.3 mg/kg orally) + 5-FU; group IV received Sema + 5-FU + chloroquine (CQ; 10 mg/kg i.p., 10 minutes prior to 5-FU);group V received 5-FU + CQ. Our results showed that 5-FU markedly increased hepatic enzyme levels, oxidative stress, inflammatory markers, and histological injury. However, pretreatment with Sema effectively counteracted these harmful effects by suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and enhancing PINK1/Parkin-mediated mitophagy. Notably, the addition of CQ, an autophagy inhibitor, abolished the protective role of Sema in autophagic flux. Furthermore, Sema reduced proinflammatory cytokines (tumor necrosis factor-α and interleukin-6), oxidative stress markers (malondialdehyde), and apoptotic markers (caspase-3), enhanced the antioxidant activity (glutathione), and promoted the activation of the phosphorylated CREB/Nrf2/HO-1 signaling pathway. In conclusion, Sema attenuates the 5-FU-induced liver injury through a multifaceted mechanism involving suppression of inflammation, oxidative stress, and apoptosis, as well as by increasing autophagic flux by inducing the phosphorylated CREB/PINK/Parkin trajectory pathway. These findings suggest that Sema holds promise as a novel therapeutic approach for preventing chemotherapy-induced liver toxicity. SIGNIFICANCE STATEMENT: Semaglutide, a GLP-1 receptor agonist, significantly mitigates 5-fluorouracil-induced hepatotoxicity in rats, suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and reducing oxidative stress and inflammation. Semaglutide also enhances mitophagy by activating the phosphorylated CREB/PINK1/Parkin pathway, aiding in the clearance of damaged mitochondria, confirmed using chloroquine, an autophagy inhibitor.
2024-08-08 | Trim47 prevents hematopoietic stem cell exhaustion during stress by regulating MAVS-mediated innate immune pathway.
The maintenance of hematopoietic stem cell (HSC) functional integrity is essential for effective hematopoietic regeneration when suffering from injuries. Studies have shown that the innate immune pathways play crucial roles in the stress response of HSCs, whereas how to precisely modulate these pathways is not well characterized. Here, we identify the E3 ubiquitin ligase tripartite motif-containing 47 (Trim47) as a negative regulator of the mitochondrial antiviral-signaling protein (MAVS)-mediated innate immune pathway in HSCs. We find that Trim47 is predominantly enriched in HSCs, and its deficiency impairs the function and survival of HSCs after exposure to 5-flurouracil (5-FU) and irradiation (IR). Mechanistically, Trim47 impedes the excessive activation of the innate immune signaling and inflammatory response via K48-linked ubiquitination and degradation of MAVS. Collectively, our findings demonstrate a role of Trim47 in preventing stress-induced hematopoietic failure and thus provide a promising avenue for treatment of related diseases in the clinic.
2022-05-25 | Inflammatory cancer associated fibroblasts decisive role in therapy resistance among rectal cancer patients
Standard cancer therapy research targets tumor cells while not considering the damage on the tumor microenvironment (TME) and its associated implications in impairing therapy response. Employing patients-derived organoids (PDOs) and matched stroma cells or a novel murine preclinical rectal cancer model of local radiotherapy, it was demonstrated that tumor cells-derived IL-1α polarizes cancer-associated fibroblasts towards an inflammatory (iCAFs) phenotype. While numerous studies in different tumor entities highlighted the molecular heterogeneity of CAFs, so far there are no clear findings on their functional heterogeneity and relevance in therapy resistance and response. The present study molecularly characterized iCAFs subpopulation among RCA patients as well as the preclinical mouse model and importantly unraveled the detailed molecular mechanism underlying their contribution to impair therapy response. Mechanistically, iCAFs were demonstrated to be characterized by an upregulation of nitric oxide synthase (iNOS) which triggered accumulation of reactive nitrogen species (RNS) and subsequently an oxidative DNA damage response (DDR). Such a baseline IL-1α-driven DNA damage further sensitized iCAFs to a p53-mediated therapy induced senescence (TIS) causing extensive extracellular matrix (ECM) changes and induction of senescence associated secretory phenotype (SASP) that favored tumor progression and hindered tumor cell death. Moreover, iCAFs reversibility and repolarization into more quiescent like phenotype was demonstrated upon IL-1 signaling inhibition by anakinra, a recombinant IL-1 receptor antagonist (IL1RA). Accordingly, treating mice with anakinra or specific deletion of Il1r1 in CAFs sensitized stroma-rich resistant tumors to chemoradiotherapy (CRT). Similarly, targeting CAFs senescence by senotherapy (venetoclax chemical) or employing Trp53 deficient mice reverted therapy resistance among non-responsive tumors in vivo by reducing ECM deposition and consequently favoring CD8+ T cells intratumoral infiltration posttherapy. Importantly, rectal cancer patients that do not completely respond to neoadjuvant therapy displayed an iCAFs senescence program post-CRT. Moreover, these patients presented a baseline increased CAFs content, a dominant iCAFs signature that correlated with poorer disease-free survival (DFS) and a significantly reduced circulating IL1RA serum levels. While reduced pretherapeutic IL1RN gene expression predicted poor prognosis among RCA patients, IL1RA serum levels were associated with rs4251961 (T/C) single nucleotide polymorphism (SNP) in the IL1RN gene. Finally, functional validation assays revealed that conditioned media of PDOs drove inflammatory polarization of fibroblasts and consequently rendered them sensitive to RNS-mediated DNA damage and TIS. Collectively, the study highlighted a crucial and novel role of a CAFs subset, iCAFs, in therapy resistance among RCA patients, shedding light on their functional relevance by identifying IL-1 signaling as an appealing target for their repolarization and successful targeting. Therefore, it makes sense to combine the newly demonstrated and thoroughly proven therapeutic approach of targeting IL-1 signaling in combination with conventional CRT and possibly immunotherapy. This might have a major impact on RCA therapy and be of immense relevance for other stroma-rich tumors.
2017-08-22 | P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate synthase (TS) targeting
Abstract Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico /chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Consequently, decrease in Histone H3K9AC and increase in H3K27me3 marks at the DPYD promoter are observed concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition and DPYD repression by p53 is dependent on DNA-dependent protein kinase (DNA-PK) and Ataxia telangiectasia mutated (ATM) signaling. In-vivo , liver specific Tp53 loss increases the conversion of 5-FU to 5-FUH 2 in plasma and elicits a diminished 5-FU therapeutic response in a syngeneic colorectal tumor model consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through repression of DPYD expression, following metabolic stress imposed by nucleotide imbalance. These findings have implications for the toxicity and efficacy of the cancer therapeutic 5-FU.
2015-06-17 | Targeted expression of BikDD combined with metronomic doxorubicin induces synergistic antitumor effect through Bax activation in hepatocellular carcinoma
Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific α-fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC.
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Drug Discovery Landscape
4 orphan drug designations for 5-fluorouracil poisoning, including 2 approved therapies.
4 orphan drug designations for 5-fluorouracil poisoning, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
filgrastim [Neupogen] | — | FDA | Approved | Amgen, Inc. |
2',3',5'-tri-O-acetyluridine | small molecules | EMA | — | Serb |
uridine triacetate | small molecules | FDA | Approved | BTG International Inc. |
Interferon alfa-2a (recombinant) | — | FDA | — | Hoffmann-La Roche, Inc. |
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