The adenosine A_2A receptor is a therapeutic target in neurological, heart and oncogenic diseases

ABSTRACT

Introduction

Following approval of antagonists in Parkinson’s disease therapy, the A_2A adenosine receptor (A_2AR) is gaining interest as a target to combat a variety of diseases.

Areas covered

This review focuses on the therapeutic potential of targeting A_2AR inside but also outside the central nervous system, more precisely to combat cardiac arrhythmias and to boost immune-based cancer therapies. The mechanism of regulation of the immune system by adenosine (Ado) is complex since several actors are involved, namely the enzymes that produce and degrade the compound and the four Ado receptors. Antagonists of A_2A or andadenosine A_2B Ado receptors lead to reduce their activation intracellular cAMP levels thus boosting immune responses. The literature search methodology consisted of reviewing the authors own collection of papers plus searches in the PubMed and Google Scholar databases from March 2021 to August 2022.

Expert opinion

There is a pending issue, namely, how to demonstrate the neuroprotective potential of A_2AR antagonists that would lead to delay neurodegenerative disease progression. In addition, A_2AR antagonists and, eventually, dual A_2A/A_2B receptor antagonists have potential in the treatment of heart arrythmias and cancer. If adequate resources are allocated, it is a matter of time to confirm whether or not these possibilities become a reality.

KEYWORDS:

• Adenosine deaminase
• adenosine receptors
• Anti-cancer immunotherapy
• arrythmias
• atrial fibrillation
• Cancer
• etrumadenant
• istradefylline
• neurodegenerative diseases
• neuroprotection

Article highlights

• An adenosine A_2A receptor antagonist, istradefylline, has been approved in the US and Japan for the treatment of Parkinson’s disease (PD) patients.

• Biomarkers to assess neuroprotection in humans are needed to demonstrate whether or not A_2A receptor antagonists are, as indicated by preclinical trials, neuroprotective in humans. This is very important because any neuroprotective action would indicate that those A_2A receptor antagonists would delay PD progression.

• A_2A receptor antagonists may be essential to treat atrial fibrillation, a disease that has no therapeutic tools to date. The main problem is the lack of adequate animal models and the large investment that would be necessary to obtain sufficient preclinical data and to produce and carry out ad hoc clinical trials.

• A_2A receptor antagonists are indeed useful in any cancer therapy that depends on mechanisms involving the cells of the immune system.

• Adenosine limits immune-mediated actions against cancer due to increased intracellular cAMP levels, that is, upon activation of adenosine A_2A and A_2B receptors.

• Dual antagonists that block both receptors are now being tested in clinical trials for both safety and efficacy in patients with different tumor types; dual compounds are primarily tested in combination with other anti-cancer therapies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the US Alzheimer’s Association (grant AARFD-17-503612) and by the Spanish MCIN/AEI/10.13039/501100011033 and, as appropriate, by ‘European Union’ ‘ERDF A way of making Europe’ or ’European Union Next Generation EU/PRTR’ (grants RTI2018-094204-B-I00, PID2020-113430RB-I00 and PID2021-126600OB-I00). The research group of the University of Barcelona is considered of excellence (grup consolidat #2017 SGR 1497) by the Regional Catalonian Government, which does not provide any specific funding for reagents or for payment of services or Open Access fees.