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Cells Oct 2023Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for...
Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine resistance. Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. Also, silencing SLC38A5 induced mitochondrial dysfunction and reduced glutamine uptake and glutathione (GSH) levels, and downregulated the expressions of GSH-related genes NRF2 and GPX4. The blockade of glutamine uptake negatively modulated the mTOR-SREBP1-SCD1 signaling pathway. Therefore, suppression of SLC38A5 triggers ferroptosis via two pathways that regulate lipid ROS levels. Similarly, we observed that knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrate that SLC38A5 could be a novel target to overcome gemcitabine resistance in PDAC therapy.
Topics: Animals; Mice; Humans; Gemcitabine; Deoxycytidine; Ferroptosis; Glutamine; Drug Resistance, Neoplasm; Cell Line, Tumor; Pancreatic Neoplasms; Amino Acid Transport Systems, Neutral
PubMed: 37887353
DOI: 10.3390/cells12202509 -
International Journal of Molecular... Jul 2023Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic... (Review)
Review
Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer's disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.
Topics: Animals; Humans; Neurodegenerative Diseases; Thiamine; Thiamine Pyrophosphate; Coenzymes
PubMed: 37511056
DOI: 10.3390/ijms241411296 -
Scientific Reports Nov 2023Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic...
Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.
Topics: Animals; Humans; Female; Breast Neoplasms; Receptors, Fibroblast Growth Factor; Receptor, Fibroblast Growth Factor, Type 2; Pyrazoles; Pyrimidines; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1; Disease Models, Animal
PubMed: 37980453
DOI: 10.1038/s41598-023-46586-y -
European Respiratory Review : An... Jun 2023The efficacy and safety of gefapixant in adults with chronic cough remain unclear. Our objective was to assess the efficacy and safety of gefapixant using updated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The efficacy and safety of gefapixant in adults with chronic cough remain unclear. Our objective was to assess the efficacy and safety of gefapixant using updated evidence.
METHODS
MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase databases were searched from inception through September 2022. Subgroup analysis based on dose of gefapixant ( ≤20, 45-50 and ≥100 mg twice daily for low, moderate and high doses, respectively) was performed to explore a potential dose-dependent effect.
RESULTS
Five studies involving seven trials showed the efficacy of moderate- or high-dose gefapixant for reducing objective 24-h cough frequency (estimated relative reduction 30.9% and 58.5%, respectively) ( primary outcome) and awake cough frequency (estimated relative reduction 47.3% and 62.8%, respectively). Night-time cough frequency was only reduced with high-dose gefapixant. Consistently, the use of moderate- or high-dose gefapixant significantly alleviated cough severity and improved cough-related quality of life, but increased the risk of all-cause adverse events (AEs), treatment-related AEs and ageusia/dysgeusia/hypogeusia. Subgroup analysis showed dose dependency in both efficacy and AEs with a cut-off dose being ≥45 mg twice daily.
CONCLUSIONS
This meta-analysis revealed dose-dependent efficacy and adverse effects of gefapixant against chronic cough. Further studies are required to investigate the feasibility of moderate-dose ( 45-50 mg twice daily) gefapixant in clinical practice.
Topics: Adult; Humans; Chronic Disease; Cough; Pyrimidines; Quality of Life; Sulfonamides; Randomized Controlled Trials as Topic
PubMed: 37197770
DOI: 10.1183/16000617.0219-2022 -
The Oncologist Aug 2023Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of... (Review)
Review
Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.
Topics: Humans; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Antineoplastic Agents; Piperazines; Pyrimidines; Benzamides; Drug Resistance, Neoplasm; Receptor, Platelet-Derived Growth Factor alpha; Proto-Oncogene Proteins c-kit; Mutation
PubMed: 37315115
DOI: 10.1093/oncolo/oyad167 -
EBioMedicine Jul 2023Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase...
BACKGROUND
Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase Like-1(UCKL1) is an enzyme involved in the pyrimidine salvage pathway. It is highly expressed in multiple cancers. But the function and underlying mechanism of UCKL1 in CRC are yet to study.
METHODS
Large-scale genomic analysis was performed to search for potential CRC players related to pyrimidine metabolism. The function of UCKL1 in CRC were examined by RNA interference coupled with in vitro and in vivo assays. GSH/GSSG assay, NADP+ assay, ROS, and Lipid peroxidation assays were performed to check the function of UCKL1 in ferroptosis. Metabolomics analyses, RNA sequencing, western blotting, and rescue assays were done to reveal the underlying mechanisms of UCKL1. Xenograft mouse model was used to examine the therapeutic potential of UCKL1 as a target in combination with other ferroptosis inducers.
FINDINGS
UCKL1 was identified to repress ferroptosis in CRC cells. It was highly expressed in CRC. It regulated CRC cells proliferation and migration. Downregulation of UCKL1 led to enhanced tumour lipid peroxidation. Intriguingly, UCKL1 reduction-mediated ferroptosis was not related to its role in catalyzing uridine monophosphate (UMP) and cytidine monophosphate (CMP) synthesis. Instead, UCKL1 stabilized Nrf2, which in turn promoted the expression of SLC7A11, a classical repressor of ferroptosis. Moreover, downregulation of UCKL1 sensitized CRC cells to GPX4 inhibitors in vitro and in vivo.
INTERPRETATION
Our study demonstrates that UCKL1 plays a non-canonical role in repressing ferroptosis through a UCKL1-Nrf2-SLC7A11 axis in CRC cells. Combinatorial strategy in targeting ferroptosis by depletion of UCKL1 and application of GPX4 inhibitors may serve as a new effective method for CRC treatment.
FUNDING
This study was supported in part by fund from National Natural Science Foundation of China (Grant No. 31970674 to PY), by the Basic and Applied Basic Research Program of Guangdong Province (Grant No. 2023A1515030245 to KL), by the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), and by National Key Clinical Discipline.
Topics: Humans; Animals; Mice; NF-E2-Related Factor 2; Biological Assay; Cell Proliferation; Disease Models, Animal; Colorectal Neoplasms; Pyrimidines
PubMed: 37343364
DOI: 10.1016/j.ebiom.2023.104650 -
Journal of Crohn's & Colitis Mar 2024Although ulcerative proctitis [UP] can dramatically impair quality of life, treatment efficacy has been poorly investigated in UP as it was historically excluded from...
BACKGROUND
Although ulcerative proctitis [UP] can dramatically impair quality of life, treatment efficacy has been poorly investigated in UP as it was historically excluded from phase 2/3 randomised controlled trials in ulcerative colitis. Our aim was to assess the effectiveness and safety of tofacitinib for the treatment of UP.
METHODS
We conducted a retrospective, multicentre study in 17 GETAID centres, including consecutive patients with UP treated with tofacitinib. The primary endpoint was steroid-free remission between Week 8 and Week 14, defined as a partial Mayo score of 2 [and no individual subscore above 1]. Secondary outcomes included clinical response and steroid-free remission after induction and at 1 year.
RESULTS
All the 35 enrolled patients previously received anti-tumour necrosis factor [TNF] therapy and 88.6% were exposed to at least two lines of biologics. At baseline, the median partial Mayo score was 7 (intequartile range [IQR] [5.5-7]). After induction [W8-W14], 42.9% and 60.0% of patients achieved steroid-free remission and clinical response, respectively. At 1 year, the steroid-free clinical remission and clinical response rates were 39.4% and 45.5%, respectively, and 51.2% [17/33] were still receiving tofacitinib treatment. Survival without tofacitinib withdrawal was estimated at 50.4% (95% confidence interval [CI] [35.5-71.6]) at 1 year. Only a lower partial Mayo at baseline was independently associated with remission at induction (0dds ratio [OR] = 0.56 for an increase of 1, (95% CI [0.33-0.95], p = 0.03). Five [14.3%] adverse events were reported, with one leading to treatment withdrawal [septic shock secondary to cholecystitis].
CONCLUSION
Tofacitinib may offer a therapeutic option for patients with refractory UP.
Topics: Humans; Tumor Necrosis Factor Inhibitors; Retrospective Studies; Quality of Life; Proctitis; Piperidines; Pyrimidines
PubMed: 37796025
DOI: 10.1093/ecco-jcc/jjad169 -
Revista Da Sociedade Brasileira de... 2023There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an... (Review)
Review
There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.
Topics: Humans; Antifungal Agents; Amphotericin B; Flucytosine; Fluconazole; Cryptococcosis; Cryptococcus neoformans
PubMed: 37493736
DOI: 10.1590/0037-8682-0121-2023 -
CPT: Pharmacometrics & Systems... Aug 2023Gefapixant, a P2X3-receptor antagonist, demonstrated objective and subjective efficacy in individuals with refractory or unexplained chronic cough. We report a...
Gefapixant, a P2X3-receptor antagonist, demonstrated objective and subjective efficacy in individuals with refractory or unexplained chronic cough. We report a population pharmacokinetic (PopPK) analysis that characterizes gefapixant pharmacokinetics (PKs), quantifies between- and within-participant variability, and evaluates the impact of intrinsic and extrinsic factors on gefapixant exposure. The PopPK model was initially developed using PK data from six phase I studies. Stepwise covariate method was utilized to identify covariates impacting PK parameters; the model was re-estimated and covariate effects were re-assessed after integrating PK data from three phase II and III studies. Simulations were conducted to evaluate the magnitude of covariate effects on gefapixant exposure. Of 1677 participants included in this data set, 1618 had evaluable PK records. Age, body weight, and sex had statistically significant, but not clinically relevant, effects on exposure. Degree of renal impairment (RI) had statistically significant and clinically relevant effects on exposure; exposure was 17% to 89% higher in those with versus without RI. Simulation results indicated that gefapixant 45 mg administered once daily to patients with severe RI has similar exposure to gefapixant 45 mg administered twice daily to patients with normal renal function. There were no significant effects of proton pump inhibitors or food. Of evaluated intrinsic and extrinsic factors, only RI had a clinically relevant effect on gefapixant exposure. Patients with mild or moderate RI do not require dosage adjustments; however, for patients with severe RI who are not on dialysis, gefapixant 45 mg once daily is recommended.
Topics: Humans; Cough; Sulfonamides; Pyrimidines; Renal Dialysis; Renal Insufficiency
PubMed: 37147897
DOI: 10.1002/psp4.12978 -
Nature Communications Feb 2024Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates...
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.
Topics: Humans; Sarcoma, Kaposi; Herpesvirus 8, Human; Glycolysis; Carcinogenesis; Pyrimidines; Nucleotides
PubMed: 38365882
DOI: 10.1038/s41467-024-45852-5