Mechanisms of adenosine‐induced cytotoxicity and their clinical and physiological implications

Abstract

Extracellular ATP (ATPo) and adenosine are cytotoxic to several cancer cell lines, suggesting their potential use for anticancer therapy. Adenosine causes cytotoxicity, either when added exogenously or when generated from ATPo hydrolysis, via mechanisms which are not mutually exclusive and which involve, adenosine receptor activation, pyrimidine starvation and/or increases in intracellular S-adenosylhomocysteine: S-adenosylmethionine ratio. Given that adenosine also appears to protect against cytotoxicity via mechanisms including immunity against damage by oxygen free radicals, an understanding of the contribution of adenosine to ATPo-induced cytotoxicity is thus crucial, when considering any potential therapeutic use for these compounds. However, such an understanding has been largely hindered by the fact that many studies have not focused enough on the possibility that both ATPo and adenosine may mediate cytotoxicity in the same system. Such studies can benefit from use a range of ATPo concentrations when assessing the contribution of adenosine to ATPo-induced cytotoxicity. Whilst future molecular and pharmacological studies are needed to establish the nature of the cytotoxic adenosine receptor, it is possible that more than just one adenosine receptor type is involved and that the cytotoxic receptor(s) type is more likely to have a low affinity for adenosine. Activation of the adenosine receptor(s) would thus lead to cytotoxicity only at relatively high adenosine concentrations, while lower adenosine concentrations mediate non-cytotoxic physiological effects.

Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms

“…On the other hand, the overall pattern of purine homeostasis is markedly deregulated in the tumor environment by hypoxia and metabolic stress, as ascertained by data on constitutively elevated levels of intratumoral ATP (7,34), the accelerated rate of nucleotide turnover (4,9,33), and the ability of solid tumors to maintain adenosine gradient, with the highest nucleoside concentrations being reported in the center (14). Therefore, it may be speculated that besides dampening antitumor immunity, the sustained exposure of tumor cells to the elevated adenosine concurrently impairs their invasiveness (present study) and at higher micromolar concentrations also retards tumor growth and proliferation (15,21). This scenario might provide a partial explanation for the well-known phenomena of the high proliferative and invasive capacities of peripheral tumor cells located in the parenchyma and stroma, whereas the core environment of the tumor is maintained in a relatively stable, "semiquiescent," state (2).…”

“…Yet another approach includes tumor treatment with adenosine as a "kindred" metabolite; however, most of the proapoptotic and antiproliferative effects of adenosine reported in studies with different malignant cells required continuous presence of supra-physiological nucleoside concentrations (0.1-20 mmol/L) in the assay mixture (15,(17)(18)(19).…”

“…Along with "classical" receptor-mediated pathways, adenosine exerts cytotoxic and other biologic effects via intrinsic mechanisms (5,15,16). Most of these effects occur at high micromolar and even millimolar nucleoside concentrations, which are at least two orders of magnitude higher than adenosine receptor affinities and generally imply the uptake of extracellular adenosine and/or its metabolites into the cells through adenosine transporters and their ensuing interconversion into AMP and further to ADP/ATP.…”

“…As a consequence of these metabolic shifts, adenosine may induce apoptosis of different malignant cells via upregulation of p53 (17) or AMP-activated protein kinase (AMPK; ref. 18) activities, translocation of apoptosis-inducing factor AMID from the cytosol into the nucleus (19), and other mitochondrial apoptotic pathways (15). Likewise, high concentrations of adenosine receptor agonists, antagonists, and other nucleoside analogues also trigger antiproliferative and cytotoxic effects on normal and leukemic cells via receptor-independent mechanisms (3,20,21), presumably acting as antimetabolites competing with natural nucleosides and inhibiting key enzymes of purine homeostasis.…”

B 12 -dependent photoresponsive protein hydrogels for controlled stem cell/protein release

“…The photodegradation of AdoB 12 in CarH does not use a typical radical mechanism, and its photolytic product is 4′,5′-anhydroadenosine instead of more common 5′-dAdo radicals (25,40). Although adenosine could lead to cytotoxicity at relatively high concentrations or after prolonged exposure, so far, there has been no direct evidence pointing to the cytotoxicity or any other side effect of its analog 4′,5′-anhydroadenosine on cell phenotypes (41). In addition, only trace amounts of unbound AdoB 12 (∼1 μM) exists in the CarH C hydrogel (8.3 wt %) given the dissociation constant K d for the AdoB 12 -CarH complex (0.8 μM) (24).…”