Purinergic receptor-mediated effects of ATP in high-grade bladder cancer.

OBJECTIVE To assess whether the antineoplastic action of extracellular ATP seen in hormone-refractory prostate cancer extends to other aggressive urological malignancies by investigating its effect in high-grade bladder cancer cells in vitro and in vivo. MATERIALS AND METHODS HT-1376 cells (human grade 3 transitional cell carcinoma) were incubated with various purinergic receptor agonists and antagonists and their effects on cell growth was examined in vitro. The presence of different P2 receptor mRNAs was determined using reverse transcriptase-polymerase chain reaction. The effect of combining ATP with the cytotoxic agent mitomycin C (MMC) was also investigated. Models of tumour outgrowth in athymic mice were used to examine the effect of ATP on tumour growth in vivo. RESULTS HT-1376 cells expressed P2X(4,5,7) and P2Y(1,2,4,6,11) receptor mRNA. ATP significantly reduced cell growth in a concentration-dependent manner via the induction of P2 receptor-mediated apoptosis. Pharmacological profiling implicated P2X(5) and/or P2Y(11) receptors in this antineoplastic response, the same receptor subtypes shown to be active in prostate adenocarcinoma, despite the differing cellular origin. ATP and MMC combined in an additive manner. Intraperitoneal injections of ATP significantly reduced the growth of implanted tumour cells by a combination of apoptosis and necrosis. CONCLUSIONS ATP effectively reduces the growth of high-grade bladder cancer cells in vitro and in vivo. This highlights the potential use of ATP in the treatment of advanced urological malignancies irrespective of the cellular origin.