Natural compounds with P2X7 receptor-modulating properties

Wolfgang Fischer; Nicole Urban; Kerstin Immig; Heike Franke; Michael Schaefer

doi:10.1007/s11302-013-9392-1

Purinergic Signalling

June 2014, Volume 10, Issue 2, pp 313–326

Natural compounds with P2X7 receptor-modulating properties

Authors
Authors and affiliations

Wolfgang FischerEmail author
Nicole Urban
Kerstin Immig
Heike Franke
Michael Schaefer

Original Article

First Online:: 27 October 2013

Received:: 18 July 2013
Accepted:: 10 October 2013

DOI: 10.1007/s11302-013-9392-1

Cite this article as:: Fischer, W., Urban, N., Immig, K. et al. Purinergic Signalling (2014) 10: 313. doi:10.1007/s11302-013-9392-1

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Abstract

The adenosine 5′-triphosphate (ATP)-gated P2X7 receptor is a membrane-bound, non-selective cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and inflammation, release of gliotransmitters and cytokines, cancer cell growth or development of neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the ATP (1 mM)-induced Ca²⁺ response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance, teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of ATP-induced Ca²⁺ entry and Yo-Pro-1 uptake was also observed in human A375 melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic acid (GA) facilitated the P2X7 response to ATP in all three cell populations. GA also enhanced the YO-PRO-1 uptake, whereas AGL did not affect the ATP-stimulated intracellular accumulation of this dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or antineoplastic drugs.

Keywords

Ion channel-coupled purinergic receptors P2X7 calcium influx Pore formation Dye permeability

Abbreviations

A-438079: 3-[[5-(2,3-Dichlorophenyl)-1H-tetrazol-1yl]methyl]pyridine hydrochloride hydrate
AZ 10606120: N-[2-[[2-[(2-Hydroxyethyl)amino]ethyl]amino]-5-quinolinyl]-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide dihydrochloride
AGL: Agelasine
[Ca²⁺]_i: Intracellular free Ca²⁺ concentration
GA: Garcinolic acid
HBS: HEPES-buffered solution
HEK_hP2X7 cells: Human embryonic kidney 293 cells stably transfected with the human P2X7 receptor
IVM: Ivermectin
PPADS: Pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate tetrasodium salt hydrate
RB2: Reactive blue
TN: Teniposide

References

1.
Coddou C, Yan Z, Obsil T, Huidobro-Toro JP, Stojilkovic SS (2011) Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev 63(3):641–683PubMedCentralPubMedCrossRefGoogle Scholar
2.
Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A (2012) Molecular and functional properties of P2X receptors—recent progress and persisting challenges. Purinergic Signal 8(3):375–417PubMedCentralPubMedCrossRefGoogle Scholar
3.
Volonté C, Apolloni S, Skaper SD, Burnstock G (2012) P2X7 receptors: channels, pores and more. CNS Neurol Disord Drug Targets 11(6):705–721PubMedCrossRefGoogle Scholar
4.
Jiang LH, Baldwin JM, Roger S, Baldwin SA (2013) Insights into the molecular mechanisms underlying mammalian P2X7 receptor functions and contributions in diseases, revealed by structural modeling and single nucleotide polymorphisms. Front Pharmacol 4:55PubMedCentralPubMedGoogle Scholar
5.
Pelegrin P, Surprenant A (2009) The P2X₇ receptor-pannexin connection to dye uptake and IL-1β release. Purinergic Signal 5(2):129–137PubMedCentralPubMedCrossRefGoogle Scholar
6.
Khakh BS, North RA (2012) Neuromodulation by extracellular ATP and P2X receptors in the CNS. Neuron 76(1):51–69PubMedCrossRefGoogle Scholar
7.
Skaper SD, Debetto P, Giusti P (2010) The P2X₇ purinergic receptor: from physiology to neuronal disorders. FASEB J 24(2):337–345PubMedCrossRefGoogle Scholar
8.
Burnstock G, Kennedy C (2011) P2X receptors in health and disease. Adv Pharmacol 61:333–372PubMedCrossRefGoogle Scholar
9.
Wiley JS, Sluyter R, Gu BJ, Stokes L, Fuller SJ (2011) The human P2X7 receptor and its role in innate immunity. Tissue Antigens 78(5):321–332PubMedCrossRefGoogle Scholar
10.
Sluyter R, Stokes L (2011) Significance of P2X7 receptor variants to human health and disease. Recent Pat DNA Gene Seq 5(1):41–54PubMedCrossRefGoogle Scholar
11.
Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X₇ receptors. J Biol Chem 276(1):125–132PubMedCrossRefGoogle Scholar
12.
Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, Brissette W, Wicks JR, Audoly L, Gabel CA (2002) Absence of the P2X₇ receptor alters leukocyte function and attenuates an inflammatory response. J Immunol 168(12):6436–6445PubMedCrossRefGoogle Scholar
13.
Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (2005) Disruption of the P2X₇ purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114(3):386–396PubMedCrossRefGoogle Scholar
14.
Romagnoli R, Baraldi PG, Cruz-Lopez O, Lopez-Cara C, Preti D, Borea PA, Gessi S (2008) The P2X₇ receptor as a therapeutic target. Expert Opin Ther Targets 12(5):647–661PubMedCrossRefGoogle Scholar
15.
Gunosewoyo H, Kassiou M (2010) P2X purinergic receptor ligands: recently patented compounds. Expert Opin Ther Pat 20(5):625–646PubMedCrossRefGoogle Scholar
16.
Stock TC, Bloom BJ, Wei N, Ishaq S, Park W, Wang X, Gupta P, Mebus CA (2012) Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol 39(4):720–727PubMedCrossRefGoogle Scholar
17.
Regen T, van Rossum D, Scheffel J, Kastriti ME, Revelo NH, Prinz M, Brück W, Hanisch UK (2011) CD14 and TRIF govern distinct responsiveness and responses in mouse microglial TLR4 challenges by structural variants of LPS. Brain Behav Immun 25(5):957–970PubMedCrossRefGoogle Scholar
18.
Nelson DW, Sarris K, Kalvin DM, Namovic MT, Grayson G, Donnelly-Roberts DL, Harris R, Honore P, Jarvis MF, Faltynek CR, Carroll WA (2008) Structure-activity relationship studies on N′-aryl carbohydrazide P2X7 antagonists. J Med Chem 51(10):3030–3044PubMedCrossRefGoogle Scholar
19.
Michel AD, Chambers LJ, Clay WC, Condreay JP, Walter DS, Chessell IP (2007) Direct labelling of the human P2X7 receptor and identification of positive and negative cooperativity of binding. Br J Pharmacol 151(1):103–114PubMedCrossRefGoogle Scholar
20.
Nörenberg W, Sobottka H, Hempel C, Plötz T, Fischer W, Schmalzing G, Schaefer M (2012) Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors. Br J Pharmacol 167(1):48–66PubMedCentralPubMedCrossRefGoogle Scholar
21.
Surprenant A, Rassendren F, Kawashima E, North RA, Buell G (1996) The cytolytic P_2Z receptor for extracellular ATP identified as a P_2X receptor (P2X₇). Science 272(5262):735–738PubMedCrossRefGoogle Scholar
22.
Carroll WA, Donnelly-Roberts D, Jarvis MF (2009) Selective P2X₇ receptor antagonists for chronic inflammation and pain. Purinergic Signal 5(1):63–73PubMedCentralPubMedCrossRefGoogle Scholar
23.
Guile SD, Alcaraz L, Birkinshaw TN, Bowers KC, Ebden MR, Furber M, Stocks MJ (2009) Antagonists of the P2X₇ receptor. From lead identification to drug development. J Med Chem 52(10):3123–3141PubMedCrossRefGoogle Scholar
24.
Friedle SA, Curet MA, Watters JJ (2010) Recent patents on novel P2X₇ receptor antagonists and their potential for reducing central nervous system inflammation. Recent Pat CNS Drug Discov 5(1):35–45PubMedCentralPubMedCrossRefGoogle Scholar
25.
Sanz JM, Di Virgilio F (2000) Kinetics and mechanism of ATP-dependent IL-1 beta release from microglial cells. J Immunol 164(9):4893–4898PubMedCrossRefGoogle Scholar
26.
Arbeloa J, Pérez-Samartín A, Gottlieb M, Matute C (2012) P2X7 receptor blockade prevents ATP excitotoxicity in neurons and reduces brain damage after ischemia. Neurobiol Dis 45(3):954–961PubMedCrossRefGoogle Scholar
27.
Ryu JK, McLarnon JG (2008) Block of purinergic P2X₇ receptor is neuroprotective in an animal model of Alzheimer’s disease. Neuroreport 19(17):1715–1719PubMedCrossRefGoogle Scholar
28.
Takenouchi T, Sekiyama K, Sekigawa A, Fujita M, Waragai M, Sugama S, Iwamaru Y, Kitani H, Hashimoto M (2010) P2X7 receptor signaling pathway as a therapeutic target for neurodegenerative diseases. Arch Immunol Ther Exp (Warsz) 58(2):91–96CrossRefGoogle Scholar
29.
Le Feuvre RA, Brough D, Touzani O, Rothwell NJ (2003) Role of P2X7 receptors in ischemic and excitotoxic brain injury in vivo. J Cereb Blood Flow Metab 23(3):381–384PubMedCrossRefGoogle Scholar
30.
White N, Butler PE, Burnstock G (2005) Human melanomas express functional P2X₇ receptors. Cell Tissue Res 321(3):411–418PubMedCrossRefGoogle Scholar
31.
White N, Knight GE, Butler PE, Burnstock G (2009) An in vivo model of melanoma: treatment with ATP. Purinergic Signal 5(3):327–333PubMedCentralPubMedCrossRefGoogle Scholar
32.
Deli T, Csernoch L (2008) Extracellular ATP and cancer: an overview with special reference to P2 purinergic receptors. Pathol Oncol Res 14(3):219–231PubMedCrossRefGoogle Scholar
33.
Farrell AW, Gadeock S, Pupovac A, Wang B, Jalilian I, Ranson M, Sluyter R (2010) P2X7 receptor activation induces cell death and CD23 shedding in human RPMI 8226 multiple myeloma cells. Biochim Biophys Acta 1800(11):1173–1182PubMedCrossRefGoogle Scholar
34.
Di Virgilio F, Ferrari D, Adinolfi E (2009) P2X₇: a growth-promoting receptor—implications for cancer. Purinergic Signal 5(2):251–256PubMedCentralPubMedCrossRefGoogle Scholar
35.
Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29(39):5346–5358PubMedCrossRefGoogle Scholar
36.
Ryu JK, Jantaratnotai N, Serrano-Perez MC, McGeer PL, McLarnon JG (2011) Block of purinergic P2X7 receptors inhibits tumor growth in a C6 glioma brain tumor animal model. J Neuropathol Exp Neurol 70(1):13–22PubMedCrossRefGoogle Scholar
37.
Jelassi B, Chantôme A, Alcaraz-Pérez F, Baroja-Mazo A, Cayuela ML, Pelegrin P, Surprenant A, Roger S (2011) P2X₇ receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness. Oncogene 30(18):2108–2122PubMedCrossRefGoogle Scholar
38.
You V (2005) Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents. Curr Pharm Des 11(13):1695–1717PubMedCrossRefGoogle Scholar
39.
Li J, Chen W, Zhang P, Li N (2006) Topoisomerase II trapping agent teniposide induces apoptosis and G2/M or S phase arrest of oral squamous cell carcinoma. World J Surg Oncol 4:41PubMedCentralPubMedCrossRefGoogle Scholar
40.
Rivera GK, Pui CH, Santana VM, Pratt CB, Crist WM (1994) Epipodophyllotoxins in the treatment of childhood cancer. Cancer Chemother Pharmacol 34(Suppl):S89–S95PubMedCrossRefGoogle Scholar
41.
Hande KR (1998) Clinical applications of anticancer drugs targeted to topoisomerase II. Biochim Biophys Acta 1400(1–3):173–184PubMedCrossRefGoogle Scholar
42.
Rodman JH, Furman WL, Sunderland M, Rivera G, Evans WE (1993) Escalating teniposide systemic exposure to increase dose intensity for pediatric cancer patients. J Clin Oncol 11(2):287–293PubMedGoogle Scholar
43.
Nagai N, Shikii T, Mihara K, Ogata H, Sasaki Y (1998) Improved high-performance liquid chromatographic analysis of teniposide in human plasma. J Chromatogr B Biomed Sci Appl 709(2):315–319PubMedCrossRefGoogle Scholar
44.
Lv M, Xu H (2011) Recent advances in semisynthesis, biosynthesis, biological activities, mode of action, and structure–activity relationship of podophyllotoxins: an update (2008–2010). Mini Rev Med Chem 11(10):901–909PubMedCrossRefGoogle Scholar
45.
Gordaliza M (2009) Terpenyl-purines from the sea. Mar Drugs 7(4):833–849PubMedCentralPubMedCrossRefGoogle Scholar
46.
Proszenyák Á, Charnock C, Hedner E, Larsson R, Bohlin L, Gundersen LL (2007) Synthesis, antimicrobial and antineoplastic activities for agelasine and agelasimine analogs with a beta-cyclocitral derived substituent. Arch Pharm Chem Life Sci 340(12):625–634CrossRefGoogle Scholar
47.
Vik A, Hedner E, Charnock C, Tangen LW, Samuelsen Ø, Larsson R, Bohlin L, Gundersen LL (2007) Antimicrobial and cytotoxic activity of agelasine and agelasimine analogs. Bioorg Med Chem 15(12):4016–4037PubMedCrossRefGoogle Scholar
48.
Vik A, Proszenyák Á, Vermeersch M, Cos P, Maes L, Gundersen LL (2009) Screening of agelasine D and analogs for inhibitory activity against pathogenic protozoa; identification of hits for visceral leishmaniasis and Chagas disease. Molecules 14(1):279–288PubMedCrossRefGoogle Scholar
49.
Sjögren M, Dahlström M, Hedner E, Jonsson PR, Vik A, Gundersen LL, Bohlin L (2008) Antifouling activity of the sponge metabolite agelasine D and synthesised analogs on Balanus improvisus. Biofouling 24(4):251–258PubMedCrossRefGoogle Scholar
50.
Roggen H, Charnock C, Burman R, Felth J, Larsson R, Bohlin L, Gundersen LL (2011) Antimicrobial and antineoplastic activities of agelasine analogs modified in the purine 2-position. Arch Pharm Chem Life Sci 344(1):50–55CrossRefGoogle Scholar
51.
Pimentel AA, Felibertt P, Sojo F, Colman L, Mayora A, Silva ML, Rojas H, Dipolo R, Suarez AI, Compagnone RS, Arvelo F, Galindo-Castro I, De Sanctis JB, Chirino P, Benaim G (2012) The marine sponge toxin agelasine B increases the intracellular Ca²⁺ concentration and induces apoptosis in human breast cancer cells (MCF-7). Cancer Chemother Pharmacol 69(1):71–83PubMedCrossRefGoogle Scholar
52.
Biswas D, Qureshi OS, Lee WY, Croudace JE, Mura M, Lammas DA (2008) ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages. BMC Immunol 9:35. doi:10.1186/1471-2172-9-35 PubMedCentralPubMedCrossRefGoogle Scholar
53.
Han QB, Wang YL, Yang L, Tso TF, Qiao CF, Song JZ, Xu LJ, Chen SL, Yang DJ, Xu HX (2006) Cytotoxic polyprenylated xanthones from the resin of Garcinia hanburyi. Chem Pharm Bull (Tokyo) 54(2):265–267CrossRefGoogle Scholar
54.
Zhai D, Jin C, Shiau CW, Kitada S, Satterthwait AC, Reed JC (2008) Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther 7(6):1639–1646PubMedCentralPubMedCrossRefGoogle Scholar
55.
Deng YX, Pan SL, Zhao SY, Wu MQ, Sun ZQ, Chen XH, Shao ZY (2012) Cytotoxic alkoxylated xanthones from the resin of Garcinia hanburyi. Fitoterapia 83(8):1548–1552PubMedCrossRefGoogle Scholar
56.
Michel AD, Chambers LJ, Walter DS (2008) Negative and positive allosteric modulators of the P2X₇ receptor. Br J Pharmacol 153(4):737–750Google Scholar

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Authors and Affiliations

Wolfgang Fischer
- 1
Email author
Nicole Urban
- 1
Kerstin Immig
- 2
Heike Franke
- 1
Michael Schaefer
- 1

1.Rudolf-Boehm-Institute of Pharmacology and ToxicologyUniversity of LeipzigLeipzigGermany
2.Institute of AnatomyUniversity of LeipzigLeipzigGermany

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Purinergic Signalling

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Natural compounds with P2X7 receptor-modulating properties

Abstract

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