Adenosine Inhibits Cell Proliferation Differently in Human Astrocytes and in Glioblastoma Cell Lines

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

“…In addition, in a study on glioblastoma, Helena Marcelino et al found that proliferation/viability of glioblastoma cells was significantly reduced after 30 μM doses of adenosine for three consecutive days. At the same time, the cocktail of adenosine receptor antagonists ( Fredholm et al, 2001 ) was administered, but the tumor suppressor effect was not affected ( Marcelino et al, 2021 ).…”

“…Some ADK inhibitors are based on 6-(het)aryl-7-deazapurine pro-nucleotides that can inhibit cell growth by strongly inhibiting ADK activity ( Spácilová et al, 2010 ), however, the mechanism of this finding has not been further investigated. Helena Marcelino et al tested the effect of two ADK inhibitors on tumor cells in experiments on glioblastoma, and the results suggested that both ITU (25 μM) and ABT702 (15 μM) affected cells proliferation/viability ( Marcelino et al, 2021 ). Co-incubation of ITU (25 μM) and adenosine (30 μM) produced a strong and similar decrease in cell proliferation in both GBM cell lines compared to ITU alone, this suggests that only 25 mM ITU may be sufficient to generate the maximum accumulation of intracellular adenosine ( Marcelino et al, 2021 ).…”

“…Helena Marcelino et al tested the effect of two ADK inhibitors on tumor cells in experiments on glioblastoma, and the results suggested that both ITU (25 μM) and ABT702 (15 μM) affected cells proliferation/viability ( Marcelino et al, 2021 ). Co-incubation of ITU (25 μM) and adenosine (30 μM) produced a strong and similar decrease in cell proliferation in both GBM cell lines compared to ITU alone, this suggests that only 25 mM ITU may be sufficient to generate the maximum accumulation of intracellular adenosine ( Marcelino et al, 2021 ). Zhang LM et al showed that 5-ITU with concentrations (1, 2, 4, 6, 8, 10 μmol/L) for 48 h could significantly inhibit proliferation and induced apoptosis in a colon cancer cell line HT-29 ( Zhang and Xie, 2015 ).…”

Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

“…At the level of the CNS, it exerts neuroprotective activity against ischemic events [ 55 ], hypoxia, and oxidative stress, and modulates the release of neurotransmitters; it is also involved in the regulation of cytokines and the production of T lymphocytes by the immune system [ 56 , 57 ]. There are two forms of adenosine: intracellular and extracellular [ 58 ], widely expressed in all tissues, and obtained by the dephosphorylation of its precursors, adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP), or by hydrolysis of S-adenosylhomocysteine (SAH) [ 59 ]. Physiologically, the intracellular concentration of adenosine is regulated by an important enzyme known as adenosine kinase (ADK), and by two transporters: the equilibrative nucleoside transporters (ENT) and the bidirectional passive transporters, which play a critical role, as they allow free movement of adenosine across the cell membrane [ 60 ], and nucleoside concentrative transporters (CNTs), Na-dependent transporters that coordinate the adenosine gradient transport [ 61 ].…”

“…In physiological conditions, adenosine, through A1AR, determined a decrease in the proliferation of astrocytes, inducing the release of neurotrophic growth factor (NGF) [ 68 ]. A3AR, however, has a low expression in the CNS, but it is highly expressed in immune cells [ 59 ], cardiac cells, epithelial cells, colon mucosa, lung parenchyma, and bronchi. It is demonstrated that A3AR is expressed in cells involved in inflammatory processes, suggesting its potential involvement in inflammatory pathologies, such as lung injury, autoimmune diseases, and eye diseases [ 69 ].…”