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