Cyclopentenyl Cytosine (CPEC): An Overview of its in vitro and in vivo Activity

Schimmel, Kirsten J. M.; Gelderblom, Hans; Guchelaar, Henk‐Jan

doi:10.2174/156800907781386579

Cited by 26 publications

(7 citation statements)

References 47 publications

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“…21 However, there is a "salvage pathway" that utilizing cytidine as substrate when the neo-synthesis pathway is deficient. 22, 23 Cytidine is utilized by several salvage pathway enzymes, including UdK1/2, CMPK, and nucleoside diphosphate kinase A and B (NME1 and NME2). 24, 25 As shown in Figure 6A, CPEC significantly induced mRNA expression of all the salvage pathway enzymes in the presence of cytidine in ECs, but not SMCs, suggesting that ECs, but not SMCs, are able to use the salvage pathway when CTPS pathway is blocked.…”

Section: Resultsmentioning

confidence: 99%

CTP Synthase 1, a Smooth Muscle–Sensitive Therapeutic Target for Effective Vascular Repair

Tang

Cui

Wang

et al. 2013

ATVB

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Objective Vascular remodeling due to smooth muscle cell (SMC) proliferation and neointima formation is a major medical challenge in cardiovascular intervention. However, anti-neointima drugs often indistinguishably block re-endothelialization, an essential step toward successful vascular repair, due to their non-specific effect on endothelial cells (EC). The objective of this study was to identify a therapeutic target that differentially regulates SMC and EC proliferation. Approach and Results By using both rat balloon-injury and mouse wire-injury models, we identified CTP synthase (CTPS) as one of the potential targets that may be used for developing therapeutics for treating neointima-related disorders. CTPS1 was induced in proliferative SMCs in vitro and neointima SMCs in vivo. Blockade of CTPS1 expression by small hairpin RNA or activity by cyclopentenyl cytosine suppressed SMC proliferation and neointima formation. Surprisingly, cyclopentenyl cytosine had much less effect on EC proliferation. Of importance, blockade of CTPS1 in vivo sustained the re-endothelialization due to induction of CTP synthesis salvage pathway enzymes nucleoside diphosphate kinase A and B in ECs. Diphosphate kinase B appeared to preserve EC proliferation via utilization of extracellular cytidine to synthesize CTP. Indeed, blockade of both CTPS1 and diphosphate kinase B suppressed EC proliferation in vitro and the re-endothelization in vivo. Conclusions Our study uncovered a fundamental difference in CTP biosynthesis between SMCs and ECs during vascular remodeling, which provided a novel strategy by using cyclopentenyl cytosine or other CTPS1 inhibitors to selectively block SMC proliferation without disturbing or even promoting re-endothelialization for effective vascular repair following injury.

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Section: Resultsmentioning

confidence: 99%

CTP Synthase 1, a Smooth Muscle–Sensitive Therapeutic Target for Effective Vascular Repair

Tang

Cui

Wang

et al. 2013

ATVB

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“…Similarly, modulating the pyrimidine ribonucleotide levels has been a widely studied approach in treating cancer. As of today, it has been examined most extensively in leukemic cell lines, but also in the context of colorectal carcinoma, brain tumor, and neuroblastoma [ 81 ]. Although dosis-related hypotension events occurred in patients with colon carcinoma treated with CPEC in Phase I trials [ 82 ], the cardiotoxicity could not be reproduced in established rat models [ 83 ].…”

Section: Discussionmentioning

confidence: 99%

New workflow predicts drug targets against SARS-CoV-2 via metabolic changes in infected cells

et al. 2023

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COVID-19 is one of the deadliest respiratory diseases, and its emergence caught the pharmaceutical industry off guard. While vaccines have been rapidly developed, treatment options for infected people remain scarce, and COVID-19 poses a substantial global threat. This study presents a novel workflow to predict robust druggable targets against emerging RNA viruses using metabolic networks and information of the viral structure and its genome sequence. For this purpose, we implemented pymCADRE and PREDICATE to create tissue-specific metabolic models, construct viral biomass functions and predict host-based antiviral targets from more than one genome. We observed that pymCADRE reduces the computational time of flux variability analysis for internal optimizations. We applied these tools to create a new metabolic network of primary bronchial epithelial cells infected with SARS-CoV-2 and identified enzymatic reactions with inhibitory effects. The most promising reported targets were from the purine metabolism, while targeting the pyrimidine and carbohydrate metabolisms seemed to be promising approaches to enhance viral inhibition. Finally, we computationally tested the robustness of our targets in all known variants of concern, verifying our targets’ inhibitory effects. Since laboratory tests are time-consuming and involve complex readouts to track processes, our workflow focuses on metabolic fluxes within infected cells and is applicable for rapid hypothesis-driven identification of potentially exploitable antivirals concerning various viruses and host cell types.

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“…Therefore, agents that affect cytoophidia formation on dividing cells may influence the distribution of this CTP synthetase enzymatic activity between daughter cells and, in this manner, affect the proliferation potential of at least one of the daughter cells. Agents that directly affect CTP synthetases include cyclopentenyl cytosine (CPEC), but whether this is a safe anticancer strategy needs to be established as cardiotoxicity has been reported in a phase I trial [ 132 ]. In addition, accumulation of UTP might lead to nucleotide imbalance as well as to high dUTP levels.…”

Section: Ctps I and Ii Inhibitorsmentioning

confidence: 99%

Modulating pyrimidine ribonucleotide levels for the treatment of cancer

Mollick

Laı́n

2020

Cancer Metab

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By providing the necessary building blocks for nucleic acids and precursors for cell membrane synthesis, pyrimidine ribonucleotides are essential for cell growth and proliferation. Therefore, depleting pyrimidine ribonucleotide pools has long been considered as a strategy to reduce cancer cell growth. Here, we review the pharmacological approaches that have been employed to modulate pyrimidine ribonucleotide synthesis and degradation routes and discuss their potential use in cancer therapy. New developments in the treatment of myeloid malignancies with inhibitors of pyrimidine ribonucleotide synthesis justify revisiting the literature as well as discussing whether targeting this metabolic pathway can be effective and sufficiently selective for cancer cells to warrant an acceptable therapeutic index in patients.

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Cyclopentenyl Cytosine (CPEC): An Overview of its in vitro and in vivo Activity

Cited by 26 publications

References 47 publications

CTP Synthase 1, a Smooth Muscle–Sensitive Therapeutic Target for Effective Vascular Repair

CTP Synthase 1, a Smooth Muscle–Sensitive Therapeutic Target for Effective Vascular Repair

New workflow predicts drug targets against SARS-CoV-2 via metabolic changes in infected cells

Modulating pyrimidine ribonucleotide levels for the treatment of cancer

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