Purines, Purinergic Receptors, and Cancer

Abstract

Purines were long thought to be restricted to the intracellular compartment, where they are used for energy transactions, nucleic acid synthesis, and a multiplicity of biochemical reactions. However, it is now clear that both adenosine and adenosine triphosphate are (i) abundant biochemical components of the tumor microenvironment, (ii) potent modulators of immune cell responses and cytokine release, and (iii) key players in host-tumor interaction. Moreover, both ATP and adenosine directly affect tumor cell growth. Adenosine is a powerful immunosuppressant (mainly acting at A2A receptors) and a modulator of cell growth (mainly acting at A3 receptors). ATP is a proinflammatory (acting at P2Y1, P2Y2, P2Y4, P2Y6, and P2Y12, and at P2X4 and P2X7 receptors), an immunosuppressant (acting at P2Y11), and a growth-promoting agent (acting at P2Y1, P2Y2, and P2X7 receptors). This complex signaling network generates an array of inhibitory and stimulatory responses that affect immune cell function, tumor growth, and metastatic dissemination. Investigation of purinergic signaling has increased our understanding of the tumor microenvironment and opened new and exciting avenues for the development of novel therapeutics. Cancer Res; 72(21); 5441-7. Ó2012 AACR.

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

“…An significant body of literature supports a role for purinergic signaling in cancer (for reviews, see [82,83]); some of the most important findings are as follows: 1) the P2X7 receptor is overexpressed in several carcinomas [83], 2) the tumoral microenvironment shows high levels of extracellular ATP [84], and 3) a variety of ectonucleotidases are present and their activity forms ADO from ATP and other adenine nucleotides; indeed, ADO has been shown to be important in cancer [85]. Recently, the role of purinergic signaling was analyzed at the onset and during regulation of EMT in transformed cells, with an emphasis on its invasive properties (Table 1).…”

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

“…Besides inflammatory conditions, there is also an interest in the therapeutic potential of purinergic compounds in a wide range of other pathologies [228] including atherosclerotic vascular diseases [229], cancer [230,231], ocular problems [232], lower urinary tract dysfunction [233], and neurodegenerative disorders including amyotropic lateral sclerosis, multiple sclerosis and Alzheimer's disease [225]. To date only two P2 receptor antagonist are marketed: the irreversible P2Y 12 receptor antagonist clopidogrel (Plavix®), which is used as an antithrombotic agent in patients with atherosclerotic vascular disease [234] and another orally active but reversible antagonist of P2Y 12 , Ticagrelor (Brilinta®), which showed to even have a greater efficacy in reducing cardiovascular death compared with clopidogrel [235].…”

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

“…2-Chloro-3-(trifluoromethyl)benzylamine was reacted with (Boc) 2 O in THF and water (1:1) without catalyst to give Bocprotected tert-butyl (2-chloro-3-(trifluoromethyl)benzyl)carbamate (6) in 90% yield. Subsequently compound 6 was methylated with CH 3 I and NaH to afford tert-butyl (2-chloro-3-(trifluoromethyl)benzyl)(methyl)carbamate (7) in 91% yield.…”

“…Analytical data was identical with Method A. (2): Compound 1 (0.47 g, 3.0 mmol) was dissolved in methanol (20 mL), and to this solution was added 2 M NaOH (3 mL, 6.0 mmol). The mixture was refluxed for 3 h, then cooled and evaporated to leave a minimal amount of water.…”

“…It is found in the immune, peripheral, and central nervous systems; implicated in ATP-mediated cell death, regulation of receptor trafficking and inflammation; and associated with various cancer, neurological and cardiovascular disorders. [1][2][3][4] Neuroinflammation is considered to play an important role in a variety of neuropathologies, such as Alzheimer's disease, Parkinson's disease and traumatic brain injury. [5][6][7] P2X 7 receptor antagonists have been developed as potential pharmaceuticals for the treatment of various diseases including neuroinflammation.…”