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Cell Metabolism Jun 2019Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to...
Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.
Topics: Animals; Carcinoma, Pancreatic Ductal; Cells, Cultured; Deoxycytidine; Drug Resistance, Neoplasm; Female; Humans; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pancreatic Neoplasms; Pyrimidines; RAW 264.7 Cells; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 30827862
DOI: 10.1016/j.cmet.2019.02.001 -
Critical Reviews in Oncology/hematology Apr 2018Fluoropyrimidines (5-fluorouracil and capecitabine) are antimetabolite drugs, widely used for the treatment of a variety of cancers, both in adjuvant and in metastatic... (Review)
Review
Fluoropyrimidines (5-fluorouracil and capecitabine) are antimetabolite drugs, widely used for the treatment of a variety of cancers, both in adjuvant and in metastatic setting. Although the most common toxicities of these drugs have been extensively studied, robust data and comprehensive characterization still lack concerning fluoropyrimidine-induced cardiotoxicity (FIC), an infrequent but potentially life-threatening toxicity. This review summarizes the current state of knowledge of FIC with special regard to proposed pathogenetic models (coronary vasospasm, endothelium and cardiomyocytes damage, toxic metabolites, dihydropyrimidine dehydrogenase deficiency); risk and predictive factors; efficacy and usefulness in detection of laboratory markers, electrocardiographic changes and cardiac imaging; and specific treatment, including a novel agent, uridine triacetate. The role of alternative chemotherapeutic options, namely raltitrexed and TAS-102, is discussed, and, lastly, we overview the most promising future directions in the research on FIC and development of diagnostic tools, including microRNA technology.
Topics: Acetates; Capecitabine; Cardiotoxicity; Cardiovascular Diseases; Drug Combinations; Fluorouracil; Humans; Neoplasms; Pyrimidines; Pyrrolidines; Quinazolines; Thiophenes; Thymine; Trifluridine; Uracil; Uridine
PubMed: 29548480
DOI: 10.1016/j.critrevonc.2018.02.002 -
Cancer Cell Jul 2017Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine...
Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.
Topics: Carbon; Deoxycytidine; Digoxin; Drug Resistance, Neoplasm; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mucin-1; Pancreatic Neoplasms; Pentose Phosphate Pathway; Prognosis; Pyrimidines; Signal Transduction; Gemcitabine
PubMed: 28697344
DOI: 10.1016/j.ccell.2017.06.004 -
Expert Opinion on Pharmacotherapy Oct 2021The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic...
INTRODUCTION
The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic options. In the last year, the soluble guanylate cyclase (sGC) stimulator, vericiguat, has drawn the attention of the medical community following the report of reduced clinical outcomes in patients with worsening chronic HF (WCHF).
AREAS COVERED
The authors review the available data on the mechanism of action of vericiguat (cyclic guanosine monophosphate (cGMP) pathway), its clinical development program, its role in HF management, and its future positioning in the therapeutic recommendations.
EXPERT OPINION
cGMP deficiency has deleterious effects on the heart and contributes to the progression of HF. Different molecules, including nitric oxide (NO) donors, phosphodiesterase inhibitors, and natriuretic peptides analogues, target the NO-sCG-cGMP pathway but have yielded conflicting results in HF patients. Vericiguat acts as a sGC stimulator thus targeting the NO-sGC-cGMP pathway by a different mechanism that complements the current pharmacotherapy for HF. Vericiguat has shown an additional statistical add-on therapy efficacy by reducing morbi-mortality in patients with WCHF. A better evaluation of HF severity might be an important determinant to guide the use of vericiguat among the available therapies.
Topics: Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Pyrimidines; Soluble Guanylyl Cyclase; Stroke Volume
PubMed: 34074190
DOI: 10.1080/14656566.2021.1937121 -
Current Medicinal Chemistry 2020Gemcitabine as a pyrimidine nucleoside analog anticancer drug has high efficacy for a broad spectrum of solid tumors. Gemcitabine is activated within tumor cells by... (Review)
Review
Gemcitabine as a pyrimidine nucleoside analog anticancer drug has high efficacy for a broad spectrum of solid tumors. Gemcitabine is activated within tumor cells by sequential phosphorylation carried out by deoxycytidine kinase to mono-, di-, and triphosphate nucleotides with the last one as the active form. But the instability, drug resistance and toxicity severely limited its utilization in clinics. In the field of medicinal chemistry, prodrugs have proven to be a very effective means for elevating drug stability and decrease undesirable side effects including the nucleoside anticancer drug such as gemcitabine. Many works have been accomplished in design and synthesis of gemcitabine prodrugs, majority of which were summarized in this review.
Topics: Antineoplastic Agents; Deoxycytidine; Humans; Neoplasms; Prodrugs; Gemcitabine
PubMed: 31419928
DOI: 10.2174/0929867326666190816230650 -
Chemical Biology & Drug Design Dec 2022Heterocyclic compounds bearing the pyrimidine core are of tremendous interest as they constitute an important class of natural and synthetic compounds exhibiting diverse... (Review)
Review
Heterocyclic compounds bearing the pyrimidine core are of tremendous interest as they constitute an important class of natural and synthetic compounds exhibiting diverse useful biological activities that hold attractive potential for clinical translation as therapeutic agents in alleviation of a myriad of diseases. Heterocycles possessing a pyrimidine scaffold have piqued tremendous interest of organic and medicinal chemists owing to their privileged bioactivities. Drugs having the pyrimidine motif have manifested to exhibit gratifying biological activity like anticancer, antiviral, anti-inflammatory, antibacterial, and antihypertensive activities. This heterocycle, being a significant endogenous component of the body, the pyrimidine derivatives can easily interact with enzymes, genetic materials, and bio components within the cell. The landscape of FDA approved drugs, presently marketed incorporating the pyrimidine scaffold continues to evolve in number and diversity. There is a tremendous surge in discovery of new targets across many diseases especially those involving emerging resistance to clinically used battery of drugs. Pyrimidine scaffolds will continue to be explored expanding their chemical space portfolio in an effort to find novel drugs impacting these targets. This review aims to provide an elaborate recapitulation of the recent trends adopted to synthesize propitious pyrimidine incorporated hits and also focuses on the clinical significance reported for functionalized pyrimidine analogues that would quintessentially aid medicinal chemists for new research explorations in this arena.
Topics: Pyrimidines; Drug Discovery; Heterocyclic Compounds
PubMed: 34914188
DOI: 10.1111/cbdd.14001 -
Nature Reviews. Cancer Jun 2019
Topics: Deoxycytidine; Humans; Macrophages; Pancreatic Neoplasms; Pyrimidines; Gemcitabine
PubMed: 31048794
DOI: 10.1038/s41568-019-0148-2 -
Angewandte Chemie (International Ed. in... Jun 2022Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that...
Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu and Mn . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules.
Topics: Aspartic Acid; Pyrimidines
PubMed: 35304939
DOI: 10.1002/anie.202117211 -
Current Neuropharmacology 2021Alzheimer's disease (AD) is a multifarious and developing neurodegenerative disorder. The treatment of AD is still a challenge and availability of drug therapy on the... (Review)
Review
Alzheimer's disease (AD) is a multifarious and developing neurodegenerative disorder. The treatment of AD is still a challenge and availability of drug therapy on the basis of symptoms is not up to the mark. In the context of existence, which is getting worse for the human brain, it is necessary to take care of all critical measures. The disease is caused due to multidirectional pathology of the body, which demands the multi-target-directed ligand (MTDL) approach. This gives hope for new drugs for AD, summarized here in with the pyrimidine based natural product inspired molecule as a lead. The review is sufficient in providing a list of chemical ingredients of the plant to cure AD and screen them against various potential targets of AD. The synthesis of a highly functionalized scaffold in one step in a single pot without isolating the intermediate is a challenging task. In few examples, we have highlighted the importance of this kind of reaction, generally known as multi-component reaction. Multi-component is a widely accepted technique by the drug discovery people due to its high atom economy. It reduces multi-step process to a one-step process, therefore the compounds library can be made in minimum time and cost. This review has highlighted the importance of multicomponent reactions by giving the example of active scaffolds of pyrimidine/fused pyrimidines. This would bring importance to the fast as well as smart synthesis of bio-relevant molecules.
Topics: Alzheimer Disease; Brain; Drug Discovery; Humans; Ligands; Pyrimidines
PubMed: 33176653
DOI: 10.2174/1570159X18666201111110136 -
Medicinal Research Reviews Sep 2020Purines and pyrimidines are essential nutrients for any cell. Most organisms are able to synthesize their own purines and pyrimidines, but this ability was lost in... (Review)
Review
Purines and pyrimidines are essential nutrients for any cell. Most organisms are able to synthesize their own purines and pyrimidines, but this ability was lost in protozoans that adapted to parasitism, leading to a great diversification in transporter activities in these organisms, especially for the acquisition of amino acids and nucleosides from their hosts throughout their life cycles. Many of these transporters have been shown to have sufficiently different substrate affinities from mammalian transporters, making them good carriers for therapeutic agents. In this review, we summarize the knowledge obtained on purine and pyrimidine activities identified in protozoan parasites to date and discuss their importance for the survival of these parasites and as drug carriers, as well as the perspectives of developments in the field.
Topics: Animals; Protozoan Proteins; Purines; Pyrimidines
PubMed: 32144812
DOI: 10.1002/med.21667