The A b action occurs

The A2b action occurs in conditions where high concentrations of adenosine is generated, so its blockage does not interfere with other physiological processes mediated by adenosine and others AR [105]. Furthermore the A3 receptor was shown to have pro-apoptotic effects on tumor lines of breast, lung, prostate and kidney cancer [139], [140], [141] in these cases blocking CD73 would be counterproductive. Finally, a recent study by Vecchio and colleagues showed that A2b receptor can be activated constitutively in prostate cell lines, i.e. independent of endogenous adenosine [142]. As A2b is overexpressed in different cancers it would be interesting to evaluate the constitutive receptor activation in other tumor lines and its contribution to tumor progression.
The A2b as therapeutic target Adenosine A2b receptor has an important role in cancer progression (immunosuppressive activity, tumor angiogenesis and metastasis). Despite the above, to date, no clinical study has evaluated the effectiveness of A2b blockade in cancer treatment. Thus A2b receptor emerges as an interesting therapeutic candidate for cancer treatment. High A2b expression in certain tumors suggests its potential role as a target to anti-cancer therapies (Table 1). In mice with melanoma, blocking A2b receptor with PSB1115 antagonist shows decrease MDSCs infiltration to tumor microenvironment and decreasing its immunomodulatory activity [143], [144]. Caffeine acts as a non-specific inhibitor of AR. It has shown diminish endothelial cell angiogenic capacity via blocking A2b receptor [145]. It has been suggested that the use of theophylline, another AR antagonist used in the treatment of ci-1033 in combination with paclitaxel improves the antimetastatic effects of this drug on melanoma cells reducing their invasive capacity [146]. theophylline also suppress A2b metastatic effects in breast cancer cells [115]. Moreover, it has been suggested that a blockade of the enzymes involved in the generation of adenosine also improves anticancer therapy [147]. Blocking CD73 inhibits metastasis of breast cancer cells [148], while blocking CD39 showed decrease tumor immunosuppressive capacity [149].
Conclusion
Conflict of interest
Acknowledgements This work was funded by Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES). Also Eduardo Fuentes thanks FONDECYT (FONDECYT Initiation N° 11140142).
Introduction The vertebrate central nervous system (CNS) is characterized by a dynamic interplay between signal transduction molecules and their cellular targets. Modulation of synaptic transmission by metabotropic or ionotropic receptors is an important source of control and dynamical adjustment in synaptic activity and can contribute to synergistic, additive or antagonistic effects [8,55]. G protein coupled receptors play a crucial role in mediating cellular responses to external stimuli, and increasing evidence suggests that they function as multiple units comprising homo/heterodimers and hetero-oligomers [8,55]. It all began in 1979–1980 in search of an explanation of where all the recently discovered neuropeptides in the brain could integrate their messages with those of classical transmitters such as the monoamines. The concept of “intramembrane receptor interactions” (receptor oligomerization) was first described by Luigi Agnati and Kjell Fuxe more than 25 years ago [3,33]. In these interactions, stimulation of one receptor changes the binding characteristics of an adjacent receptor in membrane preparations from brain tissue or transfected cells. Agnati and Fuxe postulated that an intramembrane interaction between neuropeptide and monoamine receptors could be involved, showing that substance P could modulate the high-affinity serotonin binding sites in spinal cord membrane preparations [4]. The same year, an interesting paper was published by Maggi and co-workers showing that the β-adrenergic receptor agonist isoproterenol could increase α2 adrenergic receptor binding in cortical slices, supporting the concept of intramembrane receptor–receptor interactions of GPCR [54]. Thus, not only neuropeptide and monoamine receptors were involved in intramembrane receptor–receptor interactions but also certain types of glutamate and adenosine receptors [3]. Multi-protein complexes mediate most cellular functions. In neurons, these complexes are directly involved in the neuronal transmission, which is responsible for learning, memory and developments. Over the past decades, the number and outcomes of interactions between receptors has increased continuously [3]. Recent studies have demonstrated close physical interactions where activation of one receptor affects the function of the other (Figs. 1–3).