Adenosine Signaling in Glioma Cells

  • Stefania CerutiEmail author
  • Maria P. Abbracchio
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1202)


Purines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours.


P1 receptors A3 ligands Astrocytoma Cladribine 2-Chloro-adenosine Caspase-2 Caspase-9 p53 mutations CD39 CD73 Matrix metalloproteinases Equilibrative nucleoside transporters MAP kinases 











adenosine deaminase




adenosine kinase


α,β-methylene ADP








equilibrative nucleoside transporter


glycogen synthase kinase 3β


hypoxia-inducible factor 1 α subunit









MAP kinases

mitogen-activated protein kinases


matrix metalloproteinase-9






3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


N-ethyl-carboxamide adenosine


nucleoside triphosphate diphosphohydrolase


positron emission tomography


propidium iodide


phosphatidylinositol 3-kinase


protein kinase A


protein kinase B


protein kinase C


phospholipase C


phospholipase D


Retinoblastoma protein






tumour necrosis factor alpha


vascular endothelial growth factor


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Authors and Affiliations

  1. 1.Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological SciencesUniversity of Milan – Università degli Studi di MilanoMilanItaly

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