Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman, Marc L.

doi:10.3390/cells9040956

Cited by 19 publications

(12 citation statements)

References 123 publications

(178 reference statements)

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“…This regimen has now been abandoned, but it has allowed us to identify multiple pathways activated by the drug chemical precursor, salicylate, which include an indirect elevation of extracellular Ado concentrations [53]. A similar indirect influence on the Ado system has been demonstrated for high doses of other NSAIDs (i.e., sulindac) and for sulfasalazine, a prodrug of 5-amino-salicylic acid acting as a DMARD [53,54].…”

Section: Drugs Targeting the Adenosine System In Autoimmune Disordersmentioning

confidence: 92%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.

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Section: Drugs Targeting the Adenosine System In Autoimmune Disordersmentioning

confidence: 92%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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“…In addition to the aforementioned receptor- dependent actions, adenosine also yields receptor- independent actions, which rely on metabolic and intracellular levels and the metabolism of adenosine ( Boison and Yegutkin, 2019 ). ADK plays a crucial role in the regulation of both extracellular and intracellular adenosine levels ( Jacobson and Reitman, 2020 ) and adenosine receptor-dependent and independent pathways, in coordination with other adenosine metabolizing enzymes ( Boison and Yegutkin, 2019 ). We will briefly review adenosine metabolism with a focus on the relationship between receptor-independent pathways of adenosine and DNA methylation in cancer.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Kinase on Deoxyribonucleic Acid Methylation: Adenosine Receptor-Independent Pathway in Cancer Therapy

et al. 2022

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Methylation is an important mechanism contributing to cancer pathology. Methylation of tumor suppressor genes and oncogenes has been closely associated with tumor occurrence and development. New insights regarding the potential role of the adenosine receptor-independent pathway in the epigenetic modulation of DNA methylation offer the possibility of new interventional strategies for cancer therapy. Targeting DNA methylation of cancer-related genes is a promising therapeutic strategy; drugs like 5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine) effectively reverse DNA methylation and cancer cell growth. However, current anti-methylation (or methylation modifiers) are associated with severe side effects; thus, there is an urgent need for safer and more specific inhibitors of DNA methylation (or DNA methylation modifiers). The adenosine signaling pathway is reported to be involved in cancer pathology and participates in the development of tumors by altering DNA methylation. Most recently, an adenosine metabolic clearance enzyme, adenosine kinase (ADK), has been shown to influence methylation on tumor suppressor genes and tumor development and progression. This review article focuses on recent updates on ADK and its two isoforms, and its actions in adenosine receptor-independent pathways, including methylation modification and epigenetic changes in cancer pathology.

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“…Novel experimental models and promising approaches may assist in answering these questions in the future. Jacobson and Reitman have sensibly called for further knock-out in vivo studies in order to support novel findings and re-evaluate some that were reported previously [214]. On the other hand, the question of data translatability from animal studies for human therapy persists.…”

Section: Perspectivesmentioning

confidence: 96%

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

Kotulová

Hajdúch

Džubák

2021

IJMS

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A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

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Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Cited by 19 publications

References 123 publications

Adenosine Signaling in Autoimmune Disorders

Adenosine Signaling in Autoimmune Disorders

Adenosine Kinase on Deoxyribonucleic Acid Methylation: Adenosine Receptor-Independent Pathway in Cancer Therapy

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

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