Purinergic receptor-mediated effects of adenosine 5'-triphosphate in urological malignant diseases

Abstract

Adenosine 5'-triphosphate (ATP) mediates a variety of biological functions and has been shown to play a physiological role in almost every system in the body. In the genito-urinary system, extracellular ATP has been shown to play a functional role in several different capacities, ranging from nociception in the ureter and bladder, to erectile dysfunction via its action on different 'purinergic receptors'. Discovery of the trophic effects of ATP has led to a surge in interest in this signalling system in various malignancies. To date five P2 receptor subtypes have been implicated in the growth inhibition of cancer cells, namely P2X5, P2X7, P2Y1, P2Y2 and P2Y11. Limited data are available on urological malignancies. ATP induces its anti-neoplastic effect primarily via purinergic receptor-mediated apoptosis via calcium-independent pathways, and this has been confirmed in vitro and in vivo. Studies have highlighted functional roles for the P2X5 and/or P2Y11 receptors in both hormone refractory prostate cancer and high-grade bladder cancer, although the contributory effect of pro-apoptotic P2X7 receptors remains unclear. Clinical trials have shown intravenous ATP successfully attenuates a range of systemic symptoms associated with advanced malignancies. This raises the possibility that selective targeting of specific aberrant pathways may allow for treatment of advanced primary malignancies and their systemic effects.