Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

Drill, Matthew; Jones, Nigel C.; Hunn, Martin; O’Brien, Terence J.; Monif, Mastura

doi:10.1007/s11302-021-09776-9

Cited by 33 publications

(17 citation statements)

References 113 publications

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“…In the context of cancer, P2X7R has been assigned multiple and often contrasting roles as a driver of cancer cell growth ( Di Virgilio et al, 2018 ; Scarpellino et al, 2019 ) and metastatic dissemination ( Di Virgilio et al, 2016 ; Ulrich et al, 2018 ; Pegoraro et al, 2021 ), or as a promoter of immune-mediated tumor eradication ( Adinolfi et al, 2015 ; Adinolfi et al, 2019 ; De Marchi et al, 2019 ; Lara et al, 2020 ). Interestingly, approaches based on either P2X7R antagonism or agonism have proved effective in reducing tumor growth, thus leaving many open questions on the mechanisms underlying P2X7R activity in cancer ( Adinolfi et al, 2012 ; Amoroso et al, 2015 ; Douguet et al, 2021 ; Drill et al, 2021 ). The abundance of P2X7R ligand extracellular ATP (eATP) is a well-recognized characteristic of the tumor microenvironment (TME) ( Di Virgilio et al, 2018 ; De Marchi et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Marchi

Pegoraro

Turiello

et al. 2022

Front. Cell Dev. Biol.

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ATP and adenosine are key constituents of the tumor niche where they exert opposite and complementary roles. ATP can be released in response to cell damage or actively released by tumor cells and subsequently degraded into adenosine, which accumulates within the tumor microenvironment. Notably, while ATP promotes immune eradicating responses mainly via the P2X7 receptor (P2X7R), extracellular adenosine acts as a potent immune suppressor and facilitates neovascularization thanks to the A2A receptor (A2AR). To date, studies exploring the interplay between P2X7R and A2AR in the tumor microenvironment are as yet missing. Here, we show that, in C57/bl6 P2X7 null mice inoculated with B16-F10 melanoma cells, several pro-inflammatory cytokines, including interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 12 (IL-12), interleukin 17 (IL-17), interferon gamma (IFN-γ) were significantly decreased, while the immune suppressant transforming growth factor beta (TGF-β) was almost three-fold increased. Interestingly, tumors growing in P2X7-null mice upregulated tumor-associated and splenic A2AR, suggesting that immunosuppression linked to lack of the P2X7R might depend upon A2AR overexpression. Immunohistochemical analysis showed that tumor cells’ A2AR expression was increased, especially around necrotic areas, and that vascular endothelial growth factor (VEGF) and the endothelial marker CD31 were upregulated. A2AR antagonist SCH58261 treatment reduced tumor growth similarly in the P2X7 wild type or null mice strain. However, SCH58261 reduced VEGF only in the P2X7 knock out mice, thus supporting the hypothesis of an A2AR-mediated increase in vascularization observed in the P2X7-null host. SCH58261 administration also significantly reduced intratumor TGF-β levels, thus supporting a key immune suppressive role of A2AR in our model. Altogether, these results indicate that in the absence of host P2X7R, the A2AR favors tumor growth via immune suppression and neovascularization. This study shows a novel direct correlation between P2X7R and A2AR in oncogenesis and paves the way for new combined therapies promoting anti-cancer immune responses and reducing tumor vascularization.

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Section: Introductionmentioning

confidence: 99%

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

Marchi

Pegoraro

Turiello

et al. 2022

Front. Cell Dev. Biol.

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“…Regarding GSK1482160, a phase I clinical trial has been completed to test its efficacy and tolerability for treating inflammatory pain (NCT00849134). The use of GSK1482160 as a potential therapeutic agent for the treatment of cancer has also been hypothesised [ 169 ].…”

Section: P2x7r As a Therapeutic Target In Cancer And Inflammationmentioning

confidence: 99%

The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications

Rotondo

Mazziotta

Lanzillotti

et al. 2022

Cancers

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The purinergic P2X7 receptor (P2X7R) is a transmembrane protein whose expression has been related to a variety of cellular processes, while its dysregulation has been linked to inflammation and cancer. P2X7R is expressed in cancer and immune system cell surfaces. ATP plays a key role in numerous metabolic processes due to its abundance in the tumour microenvironment. P2X7R plays an important role in cancer by interacting with ATP. The unusual property of P2X7R is that stimulation with low doses of ATP causes the opening of a permeable channel for sodium, potassium, and calcium ions, whereas sustained stimulation with high doses of ATP favours the formation of a non-selective pore. The latter effect induces a change in intracellular homeostasis that leads to cell death. This evidence suggests that P2X7R has both pro- and anti-tumour proprieties. P2X7R is increasingly recognised as a regulator of inflammation. In this review, we aimed to describe the most relevant characteristics of P2X7R function, activation, and its ligands, while also summarising the role of P2X7R activation in the context of inflammation and cancer. The currently used therapeutic approaches and clinical trials of P2X7R modulators are also described.

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“…Doxorubicin and the similar chemotherapeutic daunorubicin are part of the anthracyclines drugs family, which increase extracellular ATP levels in the tumor microenvironment [ 105 , 106 ]. Interestingly, both doxorubicin and daunorubicin cellular uptake and consequent cytotoxicity are facilitated by P2X7 receptor variant A-promoted macropore opening [ 81 , 107 ]. On the other hand, the P2X7 receptor variant B protects cells from daunorubicin toxicity and even stimulates their proliferation, probably due to a daunorubicin-dependent ATP concentration increase in the tumor microenvironment.…”

Section: Anti-p2x7 Receptor Drugs In Effectivity Studies or In Use For Cancer Therapymentioning

confidence: 99%

Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor

Rabelo

Arnaud-Sampaio

Adinolfi

et al. 2021

Cells

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The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients’ clinical management’s main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness.

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Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

Cited by 33 publications

References 113 publications

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

A2A Receptor Contributes to Tumor Progression in P2X7 Null Mice

The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications

Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor

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