Adenosine Receptors as Mediators of Both Cell Proliferation and Cell Death of Cultured Human Melanoma Cells

Adenosine displays contradictory effects on cell growth: it improves cell proliferation, but it may also induce apoptosis and impair cell survival. Following the pharmacologic characterization of adenosine receptor expression on the human melanoma cell line A375, we chose A375 as our cellular model to define how the extracellular adenosine signals are conveyed from each receptor. By using selective adenosine receptor agonists or antagonists, we found that A2A stimulation reduced cell viability and cell clone formation, whereas, at the same time, it improved cell proliferation. In support of this finding we demonstrated that the stimulation of A2A adenosine receptors stably expressed in Chinese hamster ovary cell clone reproduced deleterious effects observed in human melanoma cells. A3 stimulation counteracted A2A-induced cell death but also reduced cell proliferation. Furthermore, we found that A3 stimulation ensures cell survival. We demonstrated that adenosine triggers a survival signal via A3 receptor activation and it kills the cell through A2A receptor inducing a signaling pathway that involves protein kinase C and mitogen-activated protein kinases

Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer's Disease

The A(2A) adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer's disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-beta extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A(2A) adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A(2A) adenosine receptors in AD animal and human studies and reports the state of the art of A(2A) adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood-brain barrier in the discovery of new agents for treating CNS disorders. Considering that A(2A) receptor antagonist istradefylline is already commercially available for Parkinson's disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients

Adenosine and lymphocyte regulation

Adenosine is a potent extracellular messenger that is produced in high concentrations under metabolically unfavourable conditions. Tissue hypoxia, consequent to a compromised cellular energy status, is followed by the enhanced breakdown of ATP leading to the release of adenosine. Through the interaction with A2 and A3 membrane receptors, adenosine is devoted to the restoration of tissue homeostasis, acting as a retaliatory metabolite. Several aspects of the immune response have to be taken into consideration and even though in general it is very important to dampen inflammation, in some circumstances, such as the case of cancer, it is also necessary to increase the activity of immune cells against pathogens. Therefore, adenosine receptors that are defined as ‘sensors–of metabolic changes in the local tissue environment may be very important targets for modulation of immune responses and drugs devoted to regulating the adenosinergic system are promising in different clinical situations

Novel selective antagonist radioligands for the pharmacological study of A2B adenosine receptors

The adenosine A2B receptor is the least well characterized of the four adenosine subtypes due to the lack of potent and selective agonists and antagonists. Despite the widespread distribution of A2B receptor mRNA, little information is available with regard to their function. The characterization of A2B receptors, through radioligand binding studies, has been performed, until now, by using low-affinity and non-selective antagonists like 1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX),(4-(2-[7-amino-2-(2-furyl)-[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol ([3H]ZM 241385) and 3-(3,4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propyl-xanthine ([125I]ABOPX). Recently, high-affinity radioligands for A2B receptors, [N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide ([3H]MRS 1754), N-(2-(2-Phenyl-6-[4-(2,2,3,3-tetratritrio-3-phenylpropyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl)-acetamide ([3H]OSIP339391) and N-benzo[1,3]dioxol-5-yl-2-[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide] ([3H]MRE 2029F20), have been introduced. This minireview offers an overview of these recently developed radioligands and the most important applications of drugs towards A2B receptors

Modulation of the Akt/Ras/Raf/MEK/ERK pathway by A3 adenosine receptor

Downstream A3 receptor signalling plays an important role in the regulation of cell death and proliferation. Therefore, it is important to determine the molecular pathways involved through A3 receptor stimulation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. The crosstalk between these two pathways has also been investigated. The focus of this review centres on downstream mediators of A3 adenosine receptor signalling

“Sistemi di trasmissione: Trasmissione purinergica”, In “F. Rossi, V. Cuomo, C. Riccardi. Farmacologia. Principi di base e applicazioni terapeutiche. Edizioni Minerva Medica. IV Edizione, Torino 2020”.

“Sistemi di trasmissione: Trasmissione purinergica

A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the most common neurodegenerative pathologies. Its incidence is in dramatic growth in Western societies and there is a need of both biomarkers to support the clinical diagnosis and drugs for the treatment of AD. The diagnostic criteria of AD are based on clinical data. However, it is necessary to develop biomarkers considering the neuropathology of AD. The A2A receptor, a G-protein coupled member of the P1 family of adenosine receptors, has different functions crucial for neurodegeneration. Its activation in the hippocampal region regulates synaptic plasticity and in particular glutamate release, NMDA receptor activation and calcium influx. Additionally, it exerts effects in neuroinflammation, regulating the secretion of pro-inflammatory cytokines. In AD patients, its expression is increased in the hippocampus/entorhinal cortex more than in the frontal cortex, a phenomenon not observed in age-matched control brains, indicating an association with AD pathology. It is upregulated in peripheral blood cells of patients affected by AD, thus reflecting its increase at central neuronal level. This review offers an overview on the main AD biomarkers and the potential role of A2A adenosine receptor as a new marker and therapeutic target