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

Abstract

The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts.

• Authors: Matthew Drill, Nigel C Jones, Martin Hunn, Terence J O'Brien, Mastura Monif
• Journal: Purinergic signalling (Purinergic Signal) Vol. 17 Issue 2 Pg. 215-227 (06 2021) ISSN: 1573-9546 [Electronic] Netherlands
• PMID: 33728582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Purinergic P2X Receptor Antagonists
• Receptors, Purinergic P2X7
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Clinical Trials as Topic
• Humans
• Neoplasms (drug therapy)
• Purinergic P2X Receptor Antagonists (therapeutic use)
• Receptors, Purinergic P2X7 (drug effects)