Abstract
Background: Purinergic signalling is involved in several physiological and pathophysiological processes. P2X7 Receptor (P2X7R) is a calcium-permeable ion channel that is gaining interest as a potential therapeutic target for the treatment of different diseases including inflammation, pain, psychiatric disorders and cancer. P2X7R is ubiquitously expressed and sensitive to high ATP levels, usually found in tumor microenvironment. P2X7R regulates several cell functions, from migration to cell death, but its selective contribution to tumor progression remains controversial.
Objective: Current review was conducted to check involvement of P2X7R use in cancer treatment.
Methods: We review the most recent patents focused on the use of P2X7R in the treatment of cancer.
Results: P2X7R is an intriguing purinergic receptor that plays different roles in tumor progression.
Conclusion: Powerful strategies able to selectively interfere with its expression and function should reveal helpful in the development of new anti-cancer therapies.
Keywords: Cancer, ion channels, P2X7, purinergic receptors, purinergic signalling, tumor microenvironment.
[1]
Giuliani AL, Sarti AC, Di Virgilio F. Extracellular nucleotides and nucleosides as signalling molecules. Immunol Lett 2018.
[http://dx.doi.org/10.1016/j.imlet.2018.11.006]
[http://dx.doi.org/10.1016/j.imlet.2018.11.006]
[3]
Burnstock G, Verkhratsky A. Evolutionary origins of the purinergic signalling system. Acta Physiol 2009; 195: 415-47.
[4]
Burnstock G. Discovery of purinergic signalling, the initial resistance and current explosion of interest. Br J Pharmacol 2012; 167: 238-55.
[5]
Nishimura A, Sunggip C, Oda S, Numaga-Tomita T, Tsuda M, Nishida M. Purinergic P2Y receptors: Molecular diversity and implications for treatment of cardiovascular diseases. Pharmacol Ther 2017; 180: 113-28.
[6]
Burnstock G, Knight GE. The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal 2018; 14: 1-18.
[7]
De Marchi E, Orioli E, Dal BD. P2X7 Receptor as a Therapeutic Target. In: Advances in protein chemistry and structural biology. Academic Press 2016; 104: pp. 39-79.
[8]
Di Virgilio F, Dal Ben D, Sarti AC. The P2X7 Receptor in Infection and Inflammation. Immunity 2017; 47: 15-31.
[9]
Mehta N, Kaur M, Singh M. Purinergic receptor P2X7: A novel target for anti-inflammatory therapy. Bioorganic Med Chem 2014; 22: 54-88.
[11]
Karasawa A, Michalski K, Mikhelzon P. The P2X7 receptor forms a dye-permeable pore independent of its intracellular domain but dependent on membrane lipid composition. Elife 6
[http://dx.doi.org/10.7554/eLife.31186]
[http://dx.doi.org/10.7554/eLife.31186]
[12]
Young CNJ, Sinadinos A, Lefebvre A. A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90. Autophagy 2015; 11: 113-30.
[13]
Young CNJ, Górecki DC. P2RX7 purinoceptor as a therapeutic target: The second coming? Front Chem 2018; 6: 248.
[14]
Di Virgilio F, Schmalzing G, Markwardt F. The elusive P2X7 macropore. Trends Cell Biol 2018; 28: 392-404.
[15]
Hattori M, Gouaux E. Molecular mechanism of ATP binding and ion channel activation in P2X receptors. Nature 2012; 485: 207-12.
[16]
Pan H, Ni H, Zhang L. P2RX7-V3 is a novel oncogene that promotes tumorigenesis in uveal melanoma. Tumour Biol 2016; 37: 13533-43.
[17]
Yang YC, Chang TY, Chen TC. Functional variant of the P2X7 receptor gene is associated with human papillomavirus-16 positive cervical squamous cell carcinoma. Oncotarget 2016; 7: 82798-803.
[18]
Barden JA, Yuksel A, Pedersen J. Non-functional P2X7: A novel and ubiquitous target in human cancer. J Clin Cell Immunol 2014.
[http://dx.doi.org/10.4172/2155-9899.1000237]
[http://dx.doi.org/10.4172/2155-9899.1000237]
[19]
Gilbert S, Oliphant C, Hassan S. ATP in the tumour microenvironment drives expression of nfP2X7, a key mediator of cancer cell survival. Oncogene 2018; 1-12.
[20]
Feng YH, Li X, Wang LA. Truncated P2X7 receptor variant (P2X 7-j) endogenously expressed in cervical cancer cells antagonizes the full-length P2X7 receptor through hetero-oligomerization. J Biol Chem 2006; 281: 17228-37.
[22]
Barden JA, Sluyter R, Gu BJ. Specific detection of non-functional human P2X7receptors in HEK293 cells and B-lymphocytes. FEBS Lett 2003; 538: 159-62.
[24]
Dewhirst MW, Lee C-T, Ashcraft KA. The future of biology in driving the field of hyperthermia. Int J Hyperthermia 2016; 32: 4-13.
[25]
Acuña-Castillo C, Coddou C, Bull P. Differential role of extracellular histidines in copper, zinc, magnesium and proton modulation of the P2X7 purinergic receptor. J Neurochem 2006; 101: 17-26.
[26]
Tafani M, Di Vito M, Frati A, et al. Pro-inflammatory gene expression in solid glioblastoma microenvironment and in hypoxic stem cells from human glioblastoma. J Neuroinflamm 2011; 8(1): 32-8.
[27]
Azimi I, Beilby H, Davis FM, Marcial DL, Kenny PA, Thompson EW, et al. Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells. Mol Oncol 2016; 10: 166-78.
[28]
Burnstock G. The therapeutic potential of purinergic signalling. Biochem Pharmacol 2018; 151: 157-65.
[29]
Roger S, Pelegrin P. P2X7 receptor antagonism in the treatment of cancers. Expert Opin Investig Drugs 2011; 20: 875-80.
[30]
Hilpert K, Hubler F, Renneberg D, Stamm S. Heterocyclic amide derivatives as p2x7 receptor antagonists. US9388198 (2016)
[31]
Gunosewoyo H, Kassiou M. P2X purinergic receptor ligands: recently patented compounds. Expert Opin Ther Pat 2010; 20: 625-46.
[32]
Cieślak M, Wojtczak A. Role of purinergic receptors in the Alzheimer’s disease. Purinergic Signal 2018; •••: 1-14.
[33]
Tang Y, Yin H, Liu J, Rubini P, Illes P. P2X receptors and acupuncture analgesia. Brain Res Bull 2018.
[http://dx.doi.org/10.1016/j.brainresbull.2018.10.015]
[http://dx.doi.org/10.1016/j.brainresbull.2018.10.015]
[34]
Sesto A, Roman JP, Jimenez AI, Gascon I, Buitrago GG, Jimenez MC. Methods and compositions to inhibit P2x7 receptor expression. EP2287301 (2011)
[35]
Savio LEB, Andrade MP, Silva CG. The P2X7 receptor in inflammatory diseases: Angel or demon? Front Pharmacol 2018; 9: 52-9.
[36]
Abderrazak A, Syrovets T, Couchie D. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol 2015; 4: 296-307.
[37]
Acuna C, Capelli C, Coddou C. In vitro method for modifying the depletion profile of treg cells present in a total splenocyte population of a biological sample by means of the isolation, culturing and exposure thereof to an ATP and polymixin b medium. US20140371159 (2014)
[38]
Franses JW, Baker AB, Chitalia VC, Edelman ER. Stromal endothelial cells directly influence cancer progression. Sci Transl Med 2011; 3: 66-75.
[39]
Anari F, Ramamurthy C, Zibelman M. Impact of tumor microenvironment composition on therapeutic responses and clinical outcomes in cancer. Future Oncol 2018; 14: 1409-21.
[40]
Zuccolo E, Laforenza U, Ferulli F. Stim and Orai mediate constitutive Ca2+ entry and control endoplasmic reticulum Ca2+ refilling in primary cultures of colorectal carcinoma cells. Oncotarget 2018; 9: 31098-119.
[41]
Iamshanova O, Fiorio Pla A, Prevarskaya N. Molecular mechanisms of tumour invasion: regulation by calcium signals. J Physiol 2017; 595: 3063-75.
[42]
Cui C, Merritt R, Fu L. Targeting calcium signaling in cancer therapy. Acta Pharm Sin B 2017; 7: 3-17.
[43]
Moccia F. Endothelial Ca2+ signaling and the resistance to anticancer treatments: Partners in crime. Int J Mol Sci 2018; •••
[http://dx.doi.org/10.3390/ijms19010217]
[http://dx.doi.org/10.3390/ijms19010217]
[44]
Lodola F, Laforenza U, Cattaneo F. VEGF-induced intracellular Ca2+ oscillations are down-regulated and do not stimulate angiogenesis in breast cancer-derived endothelial colony forming cells. Oncotarget 2017; 8: 95223-46.
[45]
Poletto V, Dragoni S, Lim D, Biggiogera M, Aronica A, Cinelli M, et al. Endoplasmic reticulum Ca2+ handling and apoptotic resistance in tumor-derived endothelial colony forming cells. J Cell Biochem 2016; 117: 2260-71.
[46]
Petrillo S, Chiabrando D, Genova T, Fiorito V, Ingoglia G, Vinchi F, et al. Heme accumulation in endothelial cells impairs angiogenesis by triggering paraptosis. Cell Death Differ 2018; 25: 573-88.
[47]
Fiorio Pla A, Genova T, Pupo E. Multiple roles of protein kinase a in arachidonic acid-mediated Ca2+ entry and tumor-derived human endothelial cell migration. Mol Cancer Res 2010; 8: 1466-76.
[48]
Genova T, Grolez GP, Camillo C. TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1. J Cell Biol 2017; 216: 2107-30.
[49]
Munaron L, Genova T, Avanzato D. Targeting calcium channels to block tumor vascularization. Recent Pat Anticancer Drug Discov 2013; 8: 27-37.
[50]
Fiorio Pla A, Brossa A, Bernardini M. Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib. BMC Cancer 2014; 14: 939-47.
[51]
Petrillo S, Tolosano E, Munaron L, Genova T. Targeting metabolism to counteract tumor angiogenesis: A review of patent literature. Recent Pat Anticancer Drug Discov 2018; 13: 422-7.
[52]
Fang J, Chen X, Wang S. The expression of P2X7 receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas. Cancer Biol Ther 2015; 16: 498-510.
[53]
Moccia F, Zuccolo E, Poletto V. Endothelial progenitor cells support tumour growth and metastatisation: Implications for the resistance to anti-angiogenic therapy. Tumour Biol 2015; 36: 6603-14.
[54]
Zuccolo E, Di Buduo C, Lodola F. Stromal cell-derived factor-1α promotes endothelial colony-forming cell migration through the Ca2+ dependent activation of the extracellular signal-regulated kinase 1/2 and phosphoinositide 3-Kinase/AKT pathways. Stem Cells Dev 2018; 27: 23-34.
[55]
Amoroso F, Falzoni S, Adinolfi E. The P2X7 receptor is a key modulator of aerobic glycolysis. Cell Death Dis 2012; 3: e370-7.
[56]
Adinolfi E, Raffaghello L, Giuliani AL. Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res 2012; 72: 2957-69.
[57]
Amoroso F, Capece M, Rotondo A. The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: Evidence in experimental neuroblastoma. Oncogene 2015; 34: 5240-51.
[58]
Gu BJ, Wiley JS. Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor. Blood 2006; 107: 4946-53.
[59]
Basilico N, Magnetto C, D’Alessandro S, Panariti A, Rivolta I, Genova T, et al. Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium. Toxicol Appl Pharmacol 2015; 288: 330-8.
[60]
Ji Z, Xie Y, Guan Y, Zhang Y, Cho KS, Ji M, et al. Involvement of P2X7 receptor in proliferation and migration of human glioma cells. Biomed Res Int 2018; 8591397-107.
[61]
Adinolfi E, Melchiorri L, Falzoni S. P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood 2002; 99: 706-8.
[62]
Gómez-Villafuertes R, García-Huerta P, Díaz-Hernández JI. PI3K/Akt signaling pathway triggers P2X7 receptor expression as a pro-survival factor of neuroblastoma cells under limiting growth conditions. Sci Rep 2016; 5: 18417-23.
[63]
Amoroso F, Salaro E, Falzoni S. P2X7 targeting inhibits growth of human mesothelioma. Oncotarget 2016; 7: 49664-76.
[64]
Santos AA, Cappellari AR, de Marchi FO. Potential role of P2X7R in esophageal squamous cell carcinoma proliferation. Purinergic Signal 2017; 13: 279-92.
[65]
Giannuzzo A, Saccomano M, Napp J. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells. Int J Cancer 2016; 139: 2540-52.
[66]
Slater M, Danieletto S, Pooley M. Differentiation between cancerous and normal hyperplastic lobules in breast lesions. Breast Cancer Res Treat 2004; 83: 1-10.
[67]
Greig AVH, Burnstock G, Linge C. Expression of purinergic receptors in non-melanoma skin cancers and their functional roles in A431 cells. J Invest Dermatol 2003; 121: 315-27.
[68]
Adinolfi E, Callegari MG, Ferrari D. Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 2005; 16: 3260-72.
[69]
Gesche J, Armeanu-Ebinger S, Seitz G. New tumor marker for the rhabdomyosarcoma. US20180256743 (2018)
[70]
Di-Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene 2017; 36: 293-303.
[71]
Vázquez‐Cuevas FG, Martínez‐Ramírez AS, Robles‐Martínez L, Garay E, García‐Carrancá A, Pérez‐Montiel D, et al. Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells. J Cell Biochem 2014; 115: 1955-66.
[74]
Gilbert SM, Gidley-Baird A, Glazer S. A Phase I clinical trial demonstrates that nf-P2X7-targeted antibodies provide a novel, safe and tolerable topical therapy for basal cell carcinoma. Br J Dermatol 2017; 177: 117-24.
[76]
Avanzato D, Genova T, Fiorio Pla A. Activation of P2X7 and P2Y11 purinergic receptors inhibits migration and normalizes tumor-derived endothelial cells via cAMP signaling. Sci Rep 2016; 6: 32602-8.
[77]
Bianchi G, Vuerich M, Pellegatti P. ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment. Cell Death Dis 2017; 5: e1135-9.
[78]
Young CNJ, Chira N, Róg J. Sustained activation of P2X7 induces MMP-2-evoked cleavage and functional purinoceptor inhibition. J Mol Cell Biol 2018; 10: 229-42.
[80]
Jiang JX, Zhou JZ. Methods for treatment of primary cancer and cancer metastasis. US20150297623 (2015)
[81]
Morrone FB, Gehring MP, Nicoletti NF. Calcium channels and associated receptors in malignant brain tumor therapy. Mol Pharmacol 2016; 90: 403-9.
[82]
Prevarskaya N, Skryma R, Shuba Y. Ion channels in cancer: Are cancer hallmarks oncochannelopathies? Physiol Rev 2018; 98: 559-621.
[83]
Prevarskaya N, Skryma R, Shuba Y. Calcium in tumour metastasis: New roles for known actors. Nat Rev Cancer 2011; 11: 609-18.
[84]
Rao VR, Perez-Neut M, Kaja S. Voltage-gated ion channels in cancer cell proliferation. Cancers (Basel) 2015; 7: 849-75.
[85]
Harder BG, Blomquist MR, Wang J. Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma. Front Oncol 2018; 8: 462-9.
[86]
Territo PR, Meyer JA, Peters JS. Characterization of 11C-GSK1482160 for targeting the P2X7 receptor as a biomarker for Neuroinflammation. J Nucl Med 2017; 58: 458-65.
[87]
Beamer E, Gölöncsér F, Horváth G. Purinergic mechanisms in neuroinflammation: An update from molecules to behavior. Neuropharmacol 2016; 104: 94-104.
[88]
Chrovian CC, Rech JC, Bhattacharya A. P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders. Prog Med Chem 2014; 53: 65-100.
[89]
Friedle SA, Curet MA, Watters JJ. Recent patents on novel P2X(7) receptor antagonists and their potential for reducing central nervous system inflammation. Recent Patents CNS Drug Discov 2010; 5: 35-45.
[90]
Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders: A Review. Curr Neurol Neurosci Rep 2017; 17: 25-33.
[91]
Wang X-H, Xie X. Luo X-G Inhibiting purinergic P2X7 receptors with the antagonist brilliant blue G is neuroprotective in an intranigral lipopolysaccharide animal model of Parkinson’s disease. Mol Med Rep 2017; 15: 768-76.
[92]
Domercq M, Zabala A, Matute C. Purinergic receptors in multiple sclerosis pathogenesis. Brain Res Bull 2018; 0-1.
[93]
Cieślak M, Roszek K, Wujak M. Purinergic implication in amyotrophic lateral sclerosis: From pathological mechanisms to therapeutic perspectives. Purinergic Sig 2018.
[94]
Aquilino MS, Whyte-Fagundes P, Zoidl G. Pannexin-1 channels in epilepsy. Neurosci Lett 2017.
[http://dx.doi.org/10.1016/j.neulet.2017.09.004]
[http://dx.doi.org/10.1016/j.neulet.2017.09.004]
[95]
Pevarello P, Lohmer S. Substituted thiazole or oxazole as P2X7 receptor antagonists. US9718812 (2017)
[99]
Park JH, Kim YC. P2X7 receptor antagonists: A patent review (2010-2015). Expert Opin Ther Pat 2017; 27: 257-67.
[100]
Abdel-Magid AF. Promising therapeutic potential of P2X7 modulators. ACS Med Chem Lett 2016; 7: 348-50.
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