The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

Bartlett, Rachael; Stokes, Leanne; Sluyter, Ronald

doi:10.1124/pr.113.008003

Cited by 342 publications

(365 citation statements)

References 363 publications

(369 reference statements)

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“…The P2X7 receptor is a therapeutic target not only in cancer but in several diseases, such as rheumatoid arthritis, Alzheimer's disease, respiratory diseases and renal diseases,48, 49 and several P2X7R inhibitors are currently in phase I and II of clinical trials 48. AZ10606120 was not yet so widely used, except in a couple of subcutaneous cancer models 1, 20.…”

Section: Discussionmentioning

confidence: 99%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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The ATP‐gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu‐1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu‐1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7‐/‐ animals. PancTu‐1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120‐treated mice showed reduced bioluminescence compared to saline‐treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120‐treated tumours.

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Section: Discussionmentioning

confidence: 99%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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“…The general lack of effect of either P2X7 antagonist was not due to the preparations of BBG or A-804598, as both compounds blocked ATP-induced dye uptake into murine macrophages in this study. Moreover, both compounds were used in vivo at concentrations known to inhibit murine P2X7 [29]. In regard to IMQ-induced ear swelling, BBG may be blocking alternate molecules, such as P2X1 [30], P2X5 [31], the ATP channel pannexin-1 [32] or a voltage-gated sodium channel [33].…”

Section: Discussionmentioning

confidence: 99%

The P2X7 receptor is not essential for development of imiquimod-induced psoriasis-like inflammation in mice

Geraghty

Mansfield

Fuller

et al. 2017

Purinergic Signalling

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Psoriasis is a chronic inflammatory skin disorder, characterised by epidermal hyperplasia (acanthosis) and leukocyte infiltration of the skin. Current therapies are inadequate, highlighting the need for new therapeutic targets. The P2X7 receptor is implicated in the pathogenesis of psoriasis. This study investigated the role of P2X7 in imiquimod (IMQ)-induced psoriasis-like inflammation. Topically applied IMQ caused twofold greater ear swelling in BALB/c mice compared to C57BL/6 mice, which encode a partial loss-offunction missense mutation in the P2RX7 gene. However, there was no difference in histological skin pathology (acanthosis and leukocyte infiltration) between the two strains. IMQ treatment up-regulated P2X7 expression in skin from both mouse strains. Additionally, IMQ induced ATP release from cultured human keratinocytes, a process independent of cell death. Injection of the P2X7 antagonist Brilliant Blue G (BBG) but not A-804598 partly reduced ear swelling compared to vehicle-injected control mice. Neither antagonist altered skin pathology. Moreover, no difference in ear swelling or skin pathology was observed between C57BL/6 and P2X7 knock-out (KO) mice. Flow cytometric analysis of IMQtreated skin from C57BL/6 and P2X7 KO mice demonstrated similar leukocyte infiltration, including neutrophils, macrophages and T cells. In conclusion, this study demonstrates that P2X7 is not essential for development of IMQ-induced psoriasis-like inflammation but does not exclude a role for this receptor in psoriasis development in humans or other mouse models of this disease.

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“…Initial hopes that they may have efficacy were disappointed in Phase IIb trials in rheumatoid arthritis [97,98]. Ongoing studies include preclinical work using animal models of neuropsychiatric and neurodegenerative disease [38].…”

Section: Therapeutic Exploitationmentioning

confidence: 99%