Inhibitory effect of P2X7 receptor antagonists on in vivo tumor growth

P2X7 receptor (P2RX7) is an ATP gated ion channel localized in immunitary cells. P2RX7 plays a role in both cell death and survival, participating in necrosis and apoptosis but also in cell proliferation and tumor transformation. Recent studies reported increased P2RX7 expression in several tumors and analysis of different Affimetrix Databases retrieved high P2RX7 expression in neuroblastoma andmelanoma.We have recently demonstrated P2RX7 central role in growth and neovascularization of tumors derived from B16 murine melanoma and in ACN human neuroblastoma cell lines (Adinolfi et al., 2012). In the last years, several P2RX7 inhibitors have been developed and are actually in advanced stage trials for the therapy of inflammatory diseases. Here we suggest P2RX7 as target for antitumoral therapy. The aim of this study was to verify if systemic P2RX7 inhibition reduces tumoral growth in vivo both in human and in murine tumoral cell lines using xenograft and syngeneic mouse models, respectively. Tumors were obtained by subcutaneous injection of either B16melanoma or ACN neuroblastoma cell lines in syngeneicmice (C57Bl/6) or in nude/nude mice, respectively. B16 and ACN tumoral growth was monitored for up to 14 and 33 day, respectively. C57Bl/6 and nude/nude mice were treated with PBS (placebo) or two different P2RX7 antagonists, A74003 or AZ10606120, every 2 days from 5th day post-inoculum. B16 derived tumors excised at day 14th showed a significantly reduced volume after treatment with both A74003 (10uM) or AZ10606120 (300 nM) (~½ and~¼ compared to placebo, respectively). The decreased tumoral growth caused by P2RX7 inhibition was significantly different from day 9th post inoculum both for A74003 and AZ10606120 treatment groups. ACN derived tumors excised at day 33rd showed a significantly reduced volume after treatment with both A74003 (5 uM) and AZ10606120 (300 nM) (~¾ compared to placebo). Although not significantly different, a trend of reduction of tumoral growth, following P2RX7 inhibition, was also appreciable during in vivo measurement. In conclusion, present data show for the first time that systemic inhibition of P2RX7 affects tumoral growth both in murine and in human tumoral cell lines indicating the involvement of P2RX7 in cancer development. In this view it is convincible to identify P2RX7 as therapeutical target in cancer.