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Pharmaceuticals
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Purinergic Receptors and Ectonucleotidases as Novel Therapeutic Targets
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Purinergic Receptors and Ectonucleotidases as Novel Therapeutic Targets

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 22 May 2024 | Viewed by 5592

Special Issue Editors

Dr. Claudio Coddou

E-Mail Website
Guest Editor
1. Departamento de Ciencias Biomédicas, Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile
2. Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago, Chile
Interests: purinergic signaling; pain; cancer
Dr. Francisco Gabriel Vázquez Cuevas

E-Mail Website
Guest Editor
Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro 76230, México
Interests: purinergic signaling; ovarian carcinoma; hepatic fibrosis

Special Issue Information

Dear Colleagues,

Fifty years ago, the visionary scientist Geoffrey Burnstock proposed the purinergic signaling theory, which implied that intracellular nucleotides are released to the extracellular space where they bind to membrane receptors and ion channels and their subsequent activation leads to several physiological, and in some cases pathological, events. Although this idea had strong opposition in the beginning, purinergic signaling is now a widespread and accepted phenomenon, with several actors including G-coupled receptors (P2Y, adenosine receptors), ligand-gated ion channels (P2X receptors), ectonucleotidases that metabolize extracellular nucleotides, and proteins that are important for ATP release to the extracellular space. Purinergic signaling is involved in health and disease, participating in processes such as synaptic transmission, cardiovascular system regulation, regulation of immune-cell function, bone growth and exocrine and endocrine secretion, among others. Likewise, several pathological states are related to purinergic signaling, including cancer, as well as cardiovascular, respiratory, immune and cognitive diseases. In this Special Issue we will focus on the potential role of purinergic signaling, including receptors, nucleosidases and transport proteins, as a potential therapeutic target for these diseases.         

Dr. Claudio Coddou
Dr. Francisco Gabriel Vázquez Cuevas
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • purinergic signaling
  • P2Y receptors
  • P2X receptors
  • adenosine receptors
  • ectonucleotidases

Published Papers (4 papers)

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Research

17 pages, 2199 KiB  
Article
The Impact of A3AR Antagonism on the Differential Expression of Chemoresistance-Related Genes in Glioblastoma Stem-like Cells
by Liuba Peñate, Diego Carrillo-Beltrán, Carlos Spichiger, Alexei Cuevas-Zhbankova, Ángelo Torres-Arévalo, Pamela Silva, Hans G. Richter, Ángel Ayuso-Sacido, Rody San Martín and Claudia Quezada-Monrás
Pharmaceuticals 2024, 17(5), 579; https://doi.org/10.3390/ph17050579 - 30 Apr 2024
Viewed by 362
Abstract
Glioblastoma (GB) is the most aggressive and common primary malignant tumor of the brain and central nervous system. Without treatment, the average patient survival time is about six months, which can be extended to fifteen months with multimodal therapies. The chemoresistance observed in [...] Read more.
Glioblastoma (GB) is the most aggressive and common primary malignant tumor of the brain and central nervous system. Without treatment, the average patient survival time is about six months, which can be extended to fifteen months with multimodal therapies. The chemoresistance observed in GB is, in part, attributed to the presence of a subpopulation of glioblastoma-like stem cells (GSCs) that are characterized by heightened tumorigenic capacity and chemoresistance. GSCs are situated in hypoxic tumor niches, where they sustain and promote the stem-like phenotype and have also been correlated with high chemoresistance. GSCs have the particularity of generating high levels of extracellular adenosine (ADO), which causes the activation of the A3 adenosine receptor (A3AR) with a consequent increase in the expression and activity of genes related to chemoresistance. Therefore, targeting its components is a promising alternative for treating GB. This analysis determined genes that were up- and downregulated due to A3AR blockades under both normoxic and hypoxic conditions. In addition, possible candidates associated with chemoresistance that were positively regulated by hypoxia and negatively regulated by A3AR blockades in the same condition were analyzed. We detected three potential candidate genes that were regulated by the A3AR antagonist MRS1220 under hypoxic conditions: LIMD1, TRIB2, and TGFB1. Finally, the selected markers were correlated with hypoxia-inducible genes and with the expression of adenosine-producing ectonucleotidases. In conclusion, we detected that hypoxic conditions generate extensive differential gene expression in GSCs, increasing the expression of genes associated with chemoresistance. Furthermore, we observed that MRS1220 could regulate the expression of LIMD1, TRIB2, and TGFB1, which are involved in chemoresistance and correlate with a poor prognosis, hypoxia, and purinergic signaling. Full article
(This article belongs to the Special Issue Purinergic Receptors and Ectonucleotidases as Novel Therapeutic Targets)
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17 pages, 1866 KiB  
Article
Exploring CD39 and CD73 Expression as Potential Biomarkers in Prostate Cancer
by Carla Fernanda Furtado Gardani, Eduardo Luiz Pedrazza, Victória Santos Paz, Gabriele Goulart Zanirati, Jaderson Costa da Costa, Roberta Andrejew, Henning Ulrich, Juliete Nathali Scholl, Fabrício Figueiró, Liliana Rockenbach and Fernanda Bueno Morrone
Pharmaceuticals 2023, 16(11), 1619; https://doi.org/10.3390/ph16111619 - 16 Nov 2023
Viewed by 1637
Abstract
Prostate cancer (PC) is the most diagnosed tumor in males and ranks as the second leading cause of male mortality in the western world. The CD39 and CD73 enzymes play a crucial role in cancer regulation by degrading nucleotides and forming nucleosides. This [...] Read more.
Prostate cancer (PC) is the most diagnosed tumor in males and ranks as the second leading cause of male mortality in the western world. The CD39 and CD73 enzymes play a crucial role in cancer regulation by degrading nucleotides and forming nucleosides. This study aimed to investigate the expression of the CD39 and CD73 enzymes as potential therapeutic targets for PC. The initial part of this study retrospectively analyzed tissue samples from 23 PC patients. Using the TissueFAXSTM cytometry platform, we found significantly higher levels of CD39—labeling its intensity compared to CD73. Additionally, we observed a correlation between the Gleason score and the intensity of CD39 expression. In the prospective arm, blood samples were collected from 25 patients at the time of diagnosis and after six months of treatment to determine the expression of CD39 and CD73 in the serum extracellular vesicles (EVs) and to analyze nucleotide hydrolysis. Notably, the expression of CD39 in the EVs was significantly increased compared to the CD73 and/or combined CD39/CD73 expression levels at initial collection. Furthermore, our results demonstrated positive correlations between ADP hydrolysis and the transurethral resection and Gleason score. Understanding the role of ectonucleotidases is crucial for identifying new biomarkers in PC. Full article
(This article belongs to the Special Issue Purinergic Receptors and Ectonucleotidases as Novel Therapeutic Targets)
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15 pages, 3781 KiB  
Article
Purinergic Activation of Store-Operated Calcium Entry (SOCE) Regulates Cell Migration in Metastatic Ovarian Cancer Cells
by Esperanza Mata-Martínez, Adriana Gonzalez-Gallardo, Mauricio Díaz-Muñoz and Francisco G. Vázquez-Cuevas
Pharmaceuticals 2023, 16(7), 944; https://doi.org/10.3390/ph16070944 - 29 Jun 2023
Viewed by 945
Abstract
Store-operated calcium entry (SOCE) is an important process in calcium signaling. Its role in physiological and pathological events is well recognized. However, in cancerous systems, the importance of SOCE in relation to the degree of cancer aggressiveness, as well as its regulation by [...] Read more.
Store-operated calcium entry (SOCE) is an important process in calcium signaling. Its role in physiological and pathological events is well recognized. However, in cancerous systems, the importance of SOCE in relation to the degree of cancer aggressiveness, as well as its regulation by ligands such as purinergic molecules, are not well documented. This study aimed to characterize a differential effect of the P2Y2 receptor (promoted by UTP of 10 µM and inhibited by ARC118925XX of 1 µM) on intracellular calcium response between metastatic (SKOV-3) and non-metastatic (CAOV-3) ovarian cell lines in conditions of normal (1.5 mM) and zero extracellular calcium concentration. The sustained calcium influx observed exclusively in SKOV-3 cells was associated with the presence of SOCE (promoted by thapsigargin (74.81 ± 0.94 ΔF) and sensitive to 2-APB (20.60 ± 0.85 ΔF)), whereas its absence in CAOV-3 cells (26.2 ± 6.1 ΔF) was correlated with a low expression of ORAI1. The relevance of SOCE in metastatic SKOV-3 cells was further corroborated when 2-APB significantly inhibited (40.4 ± 2.8% of covered area) UTP-induced cell migration (54.6 ± 3.7% of covered area). In conclusion, our data suggest that SOCE activation elicited by the P2Y2 receptor is involved in the aggressiveness of ovarian cancer cells. Full article
(This article belongs to the Special Issue Purinergic Receptors and Ectonucleotidases as Novel Therapeutic Targets)
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15 pages, 4723 KiB  
Article
P2Y12 Inhibitor Monotherapy versus Conventional Dual Antiplatelet Therapy in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Meta-Analysis
by Wen-Han Feng, Yong-Chieh Chang, Yi-Hsiung Lin, Hsiao-Ling Chen, Chun-Yin Chen, Tsung-Han Lin, Tzu-Chieh Lin, Ching-Tang Chang, Hsuan-Fu Kuo, Hsiu-Mei Chang and Chih-Sheng Chu
Pharmaceuticals 2023, 16(2), 232; https://doi.org/10.3390/ph16020232 - 3 Feb 2023
Cited by 3 | Viewed by 1862
Abstract
P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) in the modern era. Clinical trials have shown that it could lower the risk of bleeding complications without increased ischemic events as compared to standard dual antiplatelet therapy [...] Read more.
P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) in the modern era. Clinical trials have shown that it could lower the risk of bleeding complications without increased ischemic events as compared to standard dual antiplatelet therapy (DAPT). However, the efficacy and safety of this novel approach among patients with acute coronary syndrome (ACS) are controversial because they have a much higher risk for recurrent ischemic events. The purpose of this study is to evaluate the efficacy and safety of this novel approach among patients with ACS. We conducted a meta-analysis of randomized controlled trials that compared P2Y12 inhibitor monotherapy with 12-month DAPT in ACS patients who underwent PCI with stent implantation. PubMed, Embase, the Cochrane library database, ClinicalTrials.gov, and other three websites were searched for data from the earliest report to July 2022. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of all-cause mortality, myocardial infarction, stent thrombosis, or stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE), defined as a composite of major bleeding and adverse cardiac and cerebrovascular events. Five randomized controlled trials with a total of 21,034 patients were included in our meta-analysis. The quantitative analysis showed a significant reduction in major or minor bleeding events in patients treated with P2Y12 inhibitor monotherapy as compared with standard DAPT(OR: 0.59, 95% CI: 0.46–0.75, p < 0.0001) without increasing the risk of MACCE (OR: 0.98, 95% CI: 0.86–1.13, p = 0.82). The NACE was favorable in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.82, 95% CI: 0.73–0.93, p = 0.002). Of note, the overall clinical benefit of P2Y12 inhibitor monotherapy was quite different between ticagrelor and clopidogrel. The incidence of NACE was significantly lower in ticagrelor monotherapy as compared with DAPT (OR: 0.79, 95% CI: 0.68–0.91), but not in clopidogrel monotherapy (OR: 1.14, 95% CI: 0.79–1.63). Both clopidogrel and ticagrelor monotherapy showed a similar reduction in bleeding complications (OR: 0.46, 95% CI: 0.22–0.94; OR: 0.60, 95% CI: 0.44–0.83, respectively). Although statistically insignificant, the incidence of MACCE was numerically higher in clopidogrel monotherapy as compared with standard DAPT (OR: 1.50, 95% CI: 0.99–2.28, p = 0.06). Based on these findings, P2Y12 inhibitor monotherapy with ticagrelor would be a better choice of medical treatment for ACS patients after PCI with stent implantation in the current era. Full article
(This article belongs to the Special Issue Purinergic Receptors and Ectonucleotidases as Novel Therapeutic Targets)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type: Research


Title: Exploring CD39 and CD73 expression as therapeutic targets and potential prognostic markers in prostate cancer

Author(s): Carla Fernanda Furtado Gardani1,3, Eduardo Pedrazza3, Victoria Santos Paz3, Gabriele Goulart Zanirati4, Jaderson Costa da Costa4, Roberta Andrejew5, Henning Ulrich5, Juliete Nathali Scholl6, Fabricio Figueiro6, Liliana Rockenbach1,3, Fernanda Bueno Morrone1,2,3,4

The Corresponding author(s): Fernanda B Morrone

Affiliation(s): 1Escola de Medicina, Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil. 2Escola de Ciências da Saúde e da Vida, Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, 90619-90, Brazil. 3Laboratório de Farmacologia Aplicada, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil. 4Instituto do Cérebro do RS, INSCER, Av. Ipiranga, Porto Alegre, RS, 906010-000, Brazil. 5Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Prof. Lineu Prestes, 748, Butantã, 05508-000, São Paulo, SP, Brazil. 6Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Abstract: Prostate cancer (PC) is the most frequently diagnosed neoplasm in males and represents the second leading cause of death in men in the Western world. It presents long periods of survival, however, patients, due to inadequate risk stratification, suffer from excessive treatments or lack thereof. Purines are signaling molecules that have diverse effects on many biological processes. CD39 and CD73 are part a family of enzymes involved in the degradation of nucleotides and the formation of nucleosides, therefore playing a key role in cancer regulation. The aim of this study was to analyze the expression of CD39 and CD73 enzymes as possible prognostic markers and/or therapeutic targets for PC. Therefore, in the first part of the study, we retrospectively analyzed tissue samples from 23 patients with PC. The expressions of the CD39 and CD73 were quantified using the TissueFAXS™ Cytometry platform. The mean age of this group was 65.4 years, with 69.5% presenting intermediate to high-grade Gleason scores. When comparing the expression profile of CD39 and CD73 we observed that the levels of CD39 labeling intensity were significantly higher than the CD73. There was a correlation between the Gleason score and the intensity of positivity for CD39 expression. In the prospective arm, blood samples were collected from 25 patients, at the time of the first diagnosis/ collection 1 and after 6 months of treatment, in order determine the expressions of CD39 and CD73 in serum extracellular vesicles (EV) and to analyze the profile of nucleotide hydrolysis in the plasma. The mean age was 68.6 years, with 52% of patients with intermediate, and 28% with high Gleason scores. Regarding EVs, there was a significant increase in CD39 expression when compared to CD73 and/or combined CD39/CD73 expressions at collection 1. The results showed that ADP hydrolysis presented positive correlations with RTU and with the Gleason score, and a negative correlation when patients underwent prostatectomy. Determining new pharmacological targets, and thus understanding the actions of ectonucleotidases in the development of PC disease is crucial.

Keywords: prostate cancer; ectonucletidases; CD39; CD73; extracellular vesicles

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