作者: Pearce, Abigail ; Ladds, Graham ; Davies, Amy ; Kalkounou, Panagoula ; Pouli, Nicole ; Pousias, Athanasios ; Lougiakis, Nikolaos ; Chorianopoulou, Anna ; Harris, Matthew ; Georgiou, Maria ; Marakos, Panagiotis ; Kolocouris, Antonios ; Huang, Xianglin ; Lambrinidis, George

Antagonism of the human adenosine A₃ receptor (hA₃R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA₃R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA₃R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while suggesting that the bromine of 39 inserts deep into the hA₃R orthosteric pocket, so highlighting the importance of rigidification of the carbonyloxycarboximidamide moiety. MD simulations highlighted the importance of rigidification of the carbonyloxycarboximidamide, while suggesting that the bromine of 39 inserts deep into the hA₃R orthosteric pocket, which was supported through mutagenesis studies 39 also selectively antagonized endogenously expressed hA₃R in nonsmall cell lung carcinoma cells, while pharmacokinetic studies indicated low toxicity enabling in vivo evaluation. We therefore suggest that 39 has potential for further development as a high-affinity hA₃R antagonist.

2017-07-01·Cancer Letters1区 · 医学

Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine/paracrine signaling of the adenosine A3 receptor

1区 · 医学

Article

作者: Merimsky, Ofer ; Akiva, Eyal ; Klein, Ofir ; Sagi-Eisenberg, Ronit ; Gorzalczany, Yaara

Mast cells (MCs) constitute an important part of the tumor microenvironment (TME). However, their underlying mechanisms of activation within the TME remain poorly understood. Here we show that recapitulating cell-to-cell contact interactions by exposing MCs to membranes derived from a number of cancer cell types, results in MC activation, evident by the increased phosphorylation of the ERK1/2 MAP kinases and Akt, in a phosphatidylinositol 3-kinase dependent fashion. Activation is unidirectional since MC derived membranes do not activate cancer cells. Stimulated ERK1/2 phosphorylation is strictly dependent on the ecto enzyme CD73 that mediates autocrine formation of adenosine, and is inhibited by knockdown of the A3 adenosine receptor (A3R) as well as by an A3R antagonist or by agonist-stimulated down-regulation of the A3R. We also show that cancer cell mediated triggering upregulates expression and stimulates secretion of interleukin 8 from the activated MCs. These findings provide evidence for a novel mode of unidirectional crosstalk between MCs and cancer cells implicating direct activation by cancer cells in MC reprogramming into a pro tumorigenic profile.

2015-07-09·Journal of Alzheimer's Disease3区 · 医学

Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation

3区 · 医学

Article

作者: Geiger, Jonathan D. ; Chen, Xuesong ; Soliman, Mahmoud L. ; Li, Shanshan ; Hui, Liang ; Agostinho, Paula ; Geiger, Nicholas H.

Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer's disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppress AβPP internalization may decrease amyloidogenic processing of AβPP. Here we tested the hypothesis that caffeine decreases Aβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosine A3 receptor (A3R) antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3Rs were findings that a specific A3R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases in AβPP protein levels in neuronal plasma membranes, increased surface expression of AβPP on neurons, and the A3R antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3R agonist decreased neuronal surface expression of AβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3R-mediated internalization of AβPP.

100 项与 A3R antagonists(National & Kapodistrian University of Athens) 相关的药物交易

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