Adenosine Receptor Antagonists to Combat Cancer and to Boost Anti-Cancer Chemotherapy and Immunotherapy

Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A1, A2A, A2B and A3, belong to the class A family of G protein-coupled receptors (GPCRs) and all four have been involved in one way or another in regulating tumor progression. Prompted by the successful anti-cancer immunotherapy, the focus was placed on the ARs more involved in regulation of immune cell differentiation and activation and that are able to establish molecular and functional interactions. This review focuses on the potential of A2A and A2B receptor antagonists in cancer control and in boosting anti-cancer chemotherapy and immunotherapy. The article also overviews the ongoing clinical trials in which A2AR and A2BR ligands are being tested in anti-cancer therapy.

• Publication year

  2021

• Venue

  Cells

• Publication date

  2021-10-21

• Fields of study

  Not labeled

• Identifiers
  DOI 10.3390/cells10112831PMCID 8616521
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Targeting the purinergic pathway in breast cancer and its therapeutic applications

  2021cited by this paper
• TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer

  2021cited by this paper
• Namodenoson in Advanced Hepatocellular Carcinoma and Child–Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial

  2021cited by this paper
• THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein‐coupled receptors

  2021cited by this paper
• Targeting the A2AR in cancer; early lessons from the clinic.

  2020cited by this paper
• Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity.

  2020cited by this paper
• Lessons from the A2A Adenosine Receptor Antagonist-Enabled Tumor Regression and Survival in Patients with Treatment-Refractory Renal Cell Cancer.

  2020cited by this paper
• A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

  2020cited by this paper
• Adenosine Metabolism: Emerging Concepts for Cancer Therapy.

  2019cited by this paper
• Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

  2019cited by this paper
• Targeting A3 and A2A adenosine receptors in the fight against cancer

  2019cited by this paper
• A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression

  2018cited by this paper
• Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC.

  2018cited by this paper
• The effect of an adenosine A2A agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma

  2018cited by this paper
• Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers

  2018cited by this paper
• Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors

  2018cited by this paper
• Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer

  2018cited by this paper
• The effect of regadenoson on the integrity of the human blood–brain barrier, a pilot study

  2017cited by this paper
• A Novel Antagonist of the Immune Checkpoint Protein Adenosine A2a Receptor Restores Tumor-Infiltrating Lymphocyte Activity in the Context of the Tumor Microenvironment

  2017cited by this paper
• A Conversation with Kurt and Rochelle Hirschhorn.

  2017cited by this paper
• Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?

  2016cited by this paper
• A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer.

  2016cited by this paper
• Adenosine deaminase regulates Treg expression in autologous T cell‐dendritic cell cocultures from patients infected with HIV‐1

  2016cited by this paper
• A Long-Term Study of Istradefylline Safety and Efficacy in Patients With Parkinson Disease

  2015cited by this paper
• TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients.

  2015cited by this paper
• Effect of Caffeine Chronically Consumed During Pregnancy on Adenosine A1 and A2A Receptors Signaling in Both Maternal and Fetal Heart from Wistar Rats

  2014cited by this paper
• An overview of adenosine A2A receptor antagonists in Parkinson's disease.

  2014cited by this paper
• Cancer Immunology at the Crossroads: Experimental Immunotherapies Hostile, Hypoxia–A2-Adenosinergic Tumor Biology as the Next Barrier to Overcome for Tumor Immunologists

  2014cited by this paper
• In vitro pharmacological profile of the A2A receptor antagonist istradefylline

  2013cited by this paper
• Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease

  2013cited by this paper
• The catalytic site structural gate of adenosine deaminase allosterically modulates ligand binding to adenosine receptors

  2013cited by this paper
• An old enzyme for current needs: adenosine deaminase and a dendritic cell vaccine for HIV

  2012cited by this paper
• A genome-wide association study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor.

  2012cited by this paper
• The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway

  2012cited by this paper
• Adenosine Deaminase Enhances the Immunogenicity of Human Dendritic Cells from Healthy and HIV-Infected Individuals

  2012cited by this paper
• Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells

  2011cited by this paper
• Adenosine receptors and cancer.

  2011cited by this paper
• Regadenoson

  2010cited by this paper
• Adenosine A2A Receptor Is Involved in Cell Surface Expression of A2B Receptor*

  2010cited by this paper
• Immunological dysfunction in HIV‐1‐infected individuals caused by impairment of adenosine deaminase‐induced costimulation of T‐cell activation

  2009cited by this paper
• Adenosine receptors and the kidney.

  2009cited by this paper
• Adenosine, adenosine A 2A antagonists, and Parkinson's disease.

  2009cited by this paper
• Adenosine deaminase enhances T‐cell response elicited by dendritic cells loaded with inactivated HIV

  2009cited by this paper
• Human adenosine deaminase as an allosteric modulator of human A1 adenosine receptor: abolishment of negative cooperativity for [3H](R)‐pia binding to the caudate nucleus

  2008cited by this paper
• Enzymatic and extraenzymatic role of adenosine deaminase 1 in T-cell-dendritic cell contacts and in alterations of the immune function.

  2007cited by this paper
• Aspects of the general biology of adenosine A2A signaling.

  2007cited by this paper
• Bone marrow transplantation for severe combined immune deficiency.

  2006cited by this paper
• CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse.

  2005cited by this paper
• Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat.

  2005cited by this paper
• Initial clinical experience with regadenoson, a novel selective A 2A agonist for pharmacologic stress single-photon emission computed tomography myocardial perfusion imaging

  2005cited by this paper
• The future of pharmacologic stress: selective A2A adenosine receptor agonists.

  2004cited by this paper
• Gene expression of adenosine receptors along the nephron.

  2004cited by this paper
• Resistance of muscle to tumor metastases: a role for a3 adenosine receptor agonists.

  2001influential reference
• Tumor-promoting functions of adenosine.

  2000cited by this paper
• Enzymatic and extraenzymatic role of ecto‐adenosine deaminase in lymphocytes

  1998cited by this paper
• Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation.

  1997cited by this paper
• Cell surface adenosine deaminase: much more than an ectoenzyme.

  1997cited by this paper
• Adenosine deaminase affects ligand‐induced signalling by interacting with cell surface adenosine receptors

  1996cited by this paper
• T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years

  1995cited by this paper
• Adenine nucleotides and adenosine metabolism in pig kidney proximal tubule membranes

  1993cited by this paper
• Surface expression of adenosine deaminase in mitogen‐stimulated lymphocytes

  1993cited by this paper
• Characterization of adenosine receptors in brush‐border membranes from pig kidney

  1992cited by this paper
• Treatment of hairy cell leukemia with deoxycoformycin (YK-176). The Deoxycoformycin (YK-176) Study Group.

  1992cited by this paper
• Adenosine receptors and signaling in the kidney.

  1991cited by this paper
• Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase.

  1987cited by this paper
• Therapy of genetic disorders.

  1987cited by this paper
• Abnormalities in S‐Adenosylhomocysteine Hydrolysis, ATP Catabolism, and Lymphoid Differentiation in Adenosine Deaminase Deficiency a

  1985cited by this paper
• The role of adenosine in the regulation of coronary blood flow.

  1980cited by this paper
• Adenosine deaminase deficiency and immunodeficiencies.

  1977cited by this paper
• Reconstitution of T-cell function in severe combined immunodeficiency disease following transplantation of early embryonic liver cells.

  1977cited by this paper
• Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency.

  1976cited by this paper
• Characterization of residual enzyme activity in fibroblasts from patients with adenosine deaminase deficiency and combined immunodeficiency: evidence for a mutant enzyme.

  1976cited by this paper
• Restoration of in-vitro lymphocyte responses with exogenous adenosine deaminase in a patient with severe combined immunodeficiency.

  1975cited by this paper
• Adenosine deaminase deficiency in a child with severe combined immunodeficiency

  1973cited by this paper
• Coronary Vasodilator Properties of Purine and Pyrimidine Derivatives

  1956cited by this paper
• The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart 1

  1929cited by this paper
• Dovepress Open Access to Scientific and Medical Research Open Access Full Text Article Pegademase Bovine (peg-ada) for the Treatment of Infants and Children with Severe Combined Immunodeficiency (scid)

  year unknowncited by this paper

• Natural bioactive molecules and chemotherapeutics synergism for enhanced cancer therapy.

  2026cites this paper
• Enzymatic and microenvironmental regulation in adenosine metabolism-mediated immunosuppression

  2026cites this paper
• Perspectives on the use of flavonoids in glioblastoma treatment by targeting adenosine receptors

  2026cites this paper
• Cannabidiol biases A2A-CB2 receptor heteromer function by decoupling β-arrestin signaling from complex formation.

  2025cites this paper
• Adenosine and Adenosine Deaminase Contrary Manifestations in Immunity

  2025cites this paper
• GPCR‐G protein signalling and its mutational landscape in cancer—Driver or passenger

  2025cites this paper
• Insights from Clinical Trials on A2A Adenosine Receptor Antagonists for Cancer Treatment.

  2025cites this paper
• ADENOZIN A1 RESEPTORLARINING OʻSMANI DAVOLASHDAGI AHAMIYATI

  2025cites this paper
• Therapeutic Applications of Nanomedicine: Recent Developments and Future Perspectives

  2024cites this paper
• The Neuroprotective Role of A2A Adenosine Purinoceptor Modulation as a Strategy Against Glioblastoma

  2024cites this paper
• Current Understanding of the Role of Adenosine Receptors in Cancer

  2024cites this paper
• A2B adenosine receptor signaling and regulation

  2024cites this paper
• Editorial: Targeting nucleotide metabolism for enhancing antitumor immunity

  2024cites this paper
• T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including Hepatocyte Growth factor

  2024cites this paper
• G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery

  2024cites this paper
• Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents.

  2024cites this paper
• Cannabidiol at Nanomolar Concentrations Negatively Affects Signaling through the Adenosine A2A Receptor

  2023cites this paper
• Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors

  2023cites this paper
• Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death-ligand 1 inhibitors in non–small cell lung cancer

  2023cites this paper
• Marginalizing the genomic architecture to identify crosstalk across cancer and neurodegeneration

  2023cites this paper
• Purinergic signaling and purine base metabolism at the crossroads between immunity, metabolism, and cancer: A review

  2023cites this paper
• A2BAR Antagonism Decreases the Glomerular Expression and Secretion of Chemoattractants for Monocytes and the Pro-Fibrotic M2 Macrophages Polarization during Diabetic Nephropathy

  2023cites this paper
• Regionally selective cardiovascular responses to adenosine A2A and A2B receptor activation

  2022cites this paper
• Immunomodulatory effect of ADO on liver tumor microenvironment

  2022cites this paper
• Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists

  2022cites this paper
• The adenosine A2A receptor is a therapeutic target in neurological, heart and oncogenic diseases

  2022influential citation
• Adenosine signaling: Optimal target for gastric cancer immunotherapy

  2022cites this paper
• Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

  2022cites this paper
• Irreversible Antagonists for the Adenosine A2B Receptor

  2022cites this paper
• Adenosine Kinase on Deoxyribonucleic Acid Methylation: Adenosine Receptor-Independent Pathway in Cancer Therapy

  2022influential citation
• Potentiating Cancer Immune Therapy via Nanomaterials and Purinergic Signaling

  2022cites this paper
• Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer’s Disease

  2022cites this paper
• Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics

  2022cites this paper
• A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

  2022cites this paper