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  • Title: Characterization of calcium-independent purinergic receptor-mediated apoptosis in hormone-refractory prostate cancer.
    Author: Shabbir M, Ryten M, Thompson C, Mikhailidis D, Burnstock G.
    Journal: BJU Int; 2008 Feb; 101(3):352-9. PubMed ID: 18005209.
    Abstract:
    OBJECTIVE: To investigate the nature of purinergic signalling in hormone-refractory prostate cancer (HRPC) cells in vitro, as extracellular ATP inhibits the growth of HRPC in vitro via the activation of P2 purinergic receptors, and to characterize which P2 receptors subtypes and secondary mechanisms are involved. MATERIALS AND METHODS: The effect of extracellular ATP on HRPC cell lines PC-3 and DU-145, and the normal prostate cell line PNT-2, were investigated. Reverse-transcription polymerase chain reaction was used to assess P2 purinergic receptors, which were pharmacologically characterized using various receptor agonists and antagonists. The effect of ATP on intracellular Ca(2+) concentration ([Ca(2+)](i)) was examined to asses its role in growth inhibition. The effect of combining ATP with the chemotherapeutic drug mitoxantrone was also assessed. RESULTS: PC-3 cells expressed mRNA for P2X(4,5,7), P2Y(1,2,4,6); DU-145 cells expressed mRNA for P2X(4,5), P2Y(1,2,4,6,11); PNT-2 cells expressed mRNA for P2X(4,5,7) and P2Y(1,2,4,6,11). ATP (10(-4)m) inhibited HRPC PC-3 cell growth by approximately 90%, an effect partially inhibited by the nonselective P2 receptor antagonists pyridoxal-5'-phosphate-6-azophenyl-2',4' disulphonic acid (PPADS) and suramin. The order of potency of agonists was: adenosine 5'-O-(3 thiotriphosphate) > ATP > benzoyl benzoyl ATP >> 2-methylthio ATP. DU-145 cells responded similarly. Pharmacological profiling implicated P2X(5) and/or P2Y(11) receptors in the antineoplastic response in HRPC. ATP induced apoptosis in a [Ca(2+)](i)-independent mechanism. ATP was significantly less effective on PNT-2 cells, which also had a different order of agonist potency. ATP combined with mitoxantrone in an additive manner in HRPC. CONCLUSIONS: ATP effectively reduces growth of HRPC cells via calcium-independent apoptosis. Pharmacological profiling indicates P2X(5) and/or P2Y(11) receptors in this process, with a different functional purinergic receptor profile and sensitivity in normal vs cancer cells.
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