Advertisement

Adenosine Signaling in Glioma Cells

  • Stefania CerutiEmail author
  • Maria P. Abbracchio
Chapter
  • 72 Downloads
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1202)

Abstract

Purines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours.

Keywords

P1 receptors A3 ligands Astrocytoma Cladribine 2-Chloro-adenosine Caspase-2 Caspase-9 p53 mutations CD39 CD73 Matrix metalloproteinases Equilibrative nucleoside transporters MAP kinases 

Abbreviations

18F-CPFPX

8-cyclopentyl-3-(3-18F-fluoropropyl)-1-propyl-xanthine

2-CA

2-chloro-adenosine

2-CdA

2-chloro-2′-deoxyadenosine

8-CPT

8-cyclo-pentyl-theophylline

ADA

adenosine deaminase

Ado

adenosine

AK

adenosine kinase

APCP

α,β-methylene ADP

CI-IB-MECA

2-chloro-N6-(3-iodobenzyl)-N-methyl-5′-carbamoyladenosine

DAG

diacylglycerol

dCyd

2′-deoxycytidine

ENT

equilibrative nucleoside transporter

GSK-3β

glycogen synthase kinase 3β

HIF-1α,

hypoxia-inducible factor 1 α subunit

IFNγ

interferon-gamma

Ino

inosine

IP3

inositol-1,4,5-trisphosphate

ITub

5-iodotubercidin

MAP kinases

mitogen-activated protein kinases

MMP-9

matrix metalloproteinase-9

MRS1220

N-(9-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)-2-phenylacetamide

MRS1706

N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NECA

N-ethyl-carboxamide adenosine

NTPDase

nucleoside triphosphate diphosphohydrolase

PET

positron emission tomography

PI

propidium iodide

PI3K

phosphatidylinositol 3-kinase

PKA

protein kinase A

PKB/Akt

protein kinase B

PKC

protein kinase C

PLC

phospholipase C

PLD

phospholipase D

pRb

Retinoblastoma protein

SAH

S-adenosyl-homocysteine

SAM

S-adenosyl-methionine

TNFα

tumour necrosis factor alpha

VEGF

vascular endothelial growth factor

References

  1. Abbracchio MP, Saffrey MJ, Höpker V, Burnstock G (1994) Modulation of astroglial cell proliferation by analogues of adenosine and ATP in primary cultures of rat striatum. Neuroscience 59:67–76.  https://doi.org/10.1016/0306-4522(94)90099-X CrossRefPubMedGoogle Scholar
  2. Abbracchio MP, Brambilla R, Ceruti S, Kim HO, von Lubitz DK, Jacobson KA, Cattabeni F (1995a) G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain. Mol Pharmacol 48:1038–1045PubMedGoogle Scholar
  3. Abbracchio MP, Ceruti S, Barbieri D, Franceschi C, Malorni W, Biondo L, Burnstock G, Cattabeni F (1995b) A novel action for adenosine: apoptosis of astroglial cells in rat brain primary cultures. Biochem Biophys Res Commun 213:908–915.  https://doi.org/10.1006/bbrc.1995.2215 CrossRefPubMedGoogle Scholar
  4. Abbracchio MP, Rainaldi G, Giammarioli AM, Ceruti S, Brambilla R, Cattabeni F, Barbieri D, Franceschi C, Jacobson KA, Malorni W (1997) The A3 adenosine receptor mediates cell spreading, reorganization of actin cytoskeleton, and distribution of Bcl-XL: studies in human astroglioma cells. Biochem Biophys Res Commun 241:297–304.  https://doi.org/10.1006/bbrc.1997.7705 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Abbracchio MP, Ceruti S, Brambilla R, Barbieri D, Camurri A, Franceschi C, Giammarioli AM, Jacobson KA, Cattabeni F, Malorni W (1998) Adenosine A3 receptors and viability of astrocytes. Drug Dev Res 45:379–386.  https://doi.org/10.1002/(SICI)1098-2299(199811/12)45:3/4<379::AID-DDR38>3.0.CO;2-Y CrossRefGoogle Scholar
  6. Abbracchio MP, Camurri A, Ceruti S, Cattabeni F, Falzano L, Giammarioli AM, Jacobson KA, Trincavelli L, Martini C, Malorni W, Fiorentini C (2001) The A3 adenosine receptor induces cytoskeleton rearrangement in human astrocytoma cells via a specific action on rho proteins. Ann N Y Acad Sci 939:63–73.  https://doi.org/10.1111/j.1749-6632.2001.tb03613.x CrossRefPubMedPubMedCentralGoogle Scholar
  7. Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA, Collaborators CGTP (2017) The concise guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol 174(Suppl 1):S17–S129.  https://doi.org/10.1111/bph.13882 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276(1):121–144.  https://doi.org/10.1111/imr.12528 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Appel E, Kazimirsky G, Ashkenazi E, Kim SG, Jacobson KA, Brodie C (2001) Roles of BCL-2 and caspase 3 in the adenosine A3 receptor-induced apoptosis. J Mol Neurosci 17:285–292.  https://doi.org/10.1385/JMN:17:3:285 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bauer A, Langen KJ, Bidmon H, Holschbach MH, Weber S, Olson RA, Coenen HH, Zilles K (2005) 18F-Cyclopentyl-3(3-18F-Fluoropropyl)-1-propyl-xanthine PET identifies changes in cerebral A1 adenosine receptor density caused by glioma invasion. J Nucl Med 46:450–454PubMedGoogle Scholar
  11. Bavaresco L, Bernardi A, Braganhol E, Cappellari AR, Rockenbach L, Farias PF, Wink MR, Delgado-Cañedo A, Battastini AM (2008) The role of ecto-5′-nucleotidase/CD73 in glioma cell line proliferation. Mol Cell Biochem 319:61–68.  https://doi.org/10.1007/s11010-008-9877-3 CrossRefPubMedGoogle Scholar
  12. Bernardi A, Bavaresco L, Wink MR, Jacques-Silva MC, Delgado-Cañedo A, Lenz G, Battastini AM (2007) Indomethacin stimulates activity and expression of ecto-5′-nucleotidase/CD73 in glioma cell lines. Eur J Pharmacol 569:8–15.  https://doi.org/10.1016/j.ejphar.2007.04.058 CrossRefPubMedGoogle Scholar
  13. Bratton SB, Salvesen GS (2010) Regulation of the Apaf-1-caspase-9 apoptosome. J Cell Sci 123:3209–3214.  https://doi.org/10.1242/jcs.073643 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cappellari AR, Vasques GJ, Bavaresco L, Braganhol E, Battastini AM (2012) Involvement of ecto-5′-nucleotidase/CD73 in U138MG glioma cell adhesion. Mol Cell Biochem 359(1–2):315–322.  https://doi.org/10.1007/s11010-011-1025-9 CrossRefPubMedGoogle Scholar
  15. Castillo CA, Albasanz JL, Fernández M, Martìn M (2007) Endogenous expression of adenosine A1, A2 and A3 receptors in rat C6 glioma cells. Neurochem Res 32:1056–1070.  https://doi.org/10.1007/s11064-006-9273-x CrossRefPubMedGoogle Scholar
  16. Castillo CA, León D, Ruiz MA, Albasanz JL, Martín M (2008) Modulation of adenosine A1 and A2A receptors in C6 glioma cells during hypoxia: involvement of endogenous adenosine. J Neurochem 105:2315–2329.  https://doi.org/10.1111/j.1471-4159.2008.05314.x CrossRefPubMedGoogle Scholar
  17. Ceruti S, Barbieri D, Veronese E, Cattabeni F, Cossarizza A, Giammarioli AM, Malorni W, Franceschi C, Abbracchio MP (1997) Different pathways of apoptosis revealed by 2-chloro-adenosine and deoxy-D-ribose in mammalian astroglial cells. J Neurosci Res 47:372–383.  https://doi.org/10.1002/(SICI)1097-4547(19970215)47:4%3C372::AID-JNR2%3E3.0.CO;2-B CrossRefPubMedGoogle Scholar
  18. Ceruti S, Franceschi C, Barbieri D, Malorni W, Camurri A, Giammarioli AM, Ambrosini A, Racagni G, Cattabeni F, Abbracchio MP (2000) Apoptosis induced by 2-chloro-adenosine and 2-chloro-2′-deoxy-adenosine in a human astrocytoma cell line: differential mechanisms and possible clinical relevance. J Neurosci Res 60:388–400.  https://doi.org/10.1002/(SICI)1097-4547(20000501)60:3<388::AID-JNR14>3.0.CO;2-V CrossRefPubMedGoogle Scholar
  19. Ceruti S, Mazzola A, Beltrami E, Passera D, Piantoni E, Cattabeni F, Abbracchio MP (2003a) Intracellular phosphorylation of chloro-adenosine analogs is a pre-requisite for activation of caspase-3 and induction of apoptosis in human astrocytoma cells. Drug Dev Res 58:396–404.  https://doi.org/10.1002/ddr.10184 CrossRefGoogle Scholar
  20. Ceruti S, Beltrami E, Matarrese P, Mazzola A, Cattabeni F, Malorni W, Abbracchio MP (2003b) A key role for caspase-2 and caspase-3 in the apoptosis induced by 2-chloro-2′-deoxy-adenosine (cladribine) and 2-chloro-adenosine in human astrocytoma cells. Mol Pharmacol 63:1437–1447.  https://doi.org/10.1124/mol.63.6.1437 CrossRefPubMedGoogle Scholar
  21. Ceruti S, Mazzola A, Abbracchio MP (2005) Resistance of human astrocytoma cells to apoptosis induced by mitochondria-damaging agents: possible implications for anticancer therapy. J Pharmacol Exp Ther 314:825–837.  https://doi.org/10.1124/jpet.105.085340 CrossRefPubMedGoogle Scholar
  22. Ceruti S, Mazzola A, Abbracchio MP (2006) Proteasome inhibitors potentiate etoposide-induced cell death in human astrocytoma cells bearing a mutated p53 isoform. J Pharmacol Exp Ther 319:1424–1434.  https://doi.org/10.1124/jpet.106.109397 CrossRefPubMedGoogle Scholar
  23. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets—what are the challenges? Nat Rev Drug Discov 12(4):265–286.  https://doi.org/10.1038/nrd3955 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Daniele S, Zappelli E, Natali L, Martini C, Trincavelli ML (2014) Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy. Cell Death Dis 5:e1539.  https://doi.org/10.1038/cddis.2014.487 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Dehnhardt M, Palm C, Vieten A, Bauer A, Pietrzyk U (2007) Quantifying the A1AR distribution in peritumoural zones around experimental F98 and C6 rat brain tumours. J Neurooncol 85:49–63.  https://doi.org/10.1007/s11060-007-9391-6 CrossRefPubMedGoogle Scholar
  26. Dhanasekaran DN, Reddy EP (2017) JNK-signaling: a multiplexing hub in programmed cell death. Genes Cancer 8(9–10):682–694.  https://doi.org/10.18632/genesandcancer.155 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Dighiero G (1996) Adverse and beneficial immunological effects of purine nucleoside analogues. Hematol Cell Ther 38:S75–S81PubMedGoogle Scholar
  28. Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R (2006) Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13(7):1238–1241.  https://doi.org/10.1038/sj.cdd.4401872 CrossRefPubMedGoogle Scholar
  29. Fiebich BL, Akundi RS, Biber K, Hamke M, Schmidt C, Butcher RD, van Calker D, Willmroth F (2005) IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C. Neurochem Int 46:501–512.  https://doi.org/10.1016/j.neuint.2004.11.009 CrossRefPubMedGoogle Scholar
  30. Figueiró F, de Oliveira CP, Bergamin LS, Rockenbach L, Mendes FB, Jandrey EH, Moritz CE, Pettenuzzo LF, Sévigny J, Guterres SS, Pohlmann AR, Battastini AM (2016) Methotrexate up-regulates ecto-5′-nucleotidase/CD73 and reduces the frequency of T lymphocytes in the glioblastoma microenvironment. Purinergic Signal 12(2):303–312.  https://doi.org/10.1007/s11302-016-9505-8 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Fishman P, Bar-Yehuda S, Madi L, Cohn I (2002) A3 adenosine receptor as a target for cancer therapy. Anti-Cancer Drugs 13:437–443CrossRefGoogle Scholar
  32. Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Müller CE (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors – an update. Pharm Rev 63:1–34.  https://doi.org/10.1124/pr.110.003285 CrossRefPubMedGoogle Scholar
  33. Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB, Carson DA, Leoni LM (2000) Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 96:3537–3543CrossRefGoogle Scholar
  34. Gessi S, Merighi S, Varani K, Leung E, Mac Lennan S, Borea PA (2008) The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol Ther 117:123–140.  https://doi.org/10.1016/j.pharmthera.2007.09.002 CrossRefPubMedGoogle Scholar
  35. Gessi S, Sacchetto V, Fogli E, Merighi S, Varani K, Baraldi PG, Tabrizi MA, Leung E, Maclennan S, Borea PA (2010) Modulation of metalloproteinase-9 in U87MG glioblastoma cells by A3 adenosine receptors. Biochem Pharmacol 79:1483–1495.  https://doi.org/10.1016/j.bcp.2010.01.009 CrossRefPubMedGoogle Scholar
  36. Gessi S, Merighi S, Sacchetto V, Simioni C, Borea PA (2011) Adenosine receptors and cancer. Biochim Biophys Acta 1808(5):1400–1412.  https://doi.org/10.1016/j.bbamem.2010.09.020 CrossRefPubMedGoogle Scholar
  37. Giagkousiklidis S, Vogler M, Westhoff MA, Kasperczyk H, Debatin KM, Fulda S (2005) Sensitization for gamma-irradiation-induced apoptosis by second mitochondria-derived activator of caspase. Cancer Res 65:10502–10513.  https://doi.org/10.1158/0008-5472.CAN-05-0866 CrossRefPubMedGoogle Scholar
  38. Gire V, Dulic V (2015) Senescence from G2 arrest, revisited. Cell Cycle 14(3):297–304.  https://doi.org/10.1080/15384101.2014.1000134 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Holmøy T, Torkildsen Ø, Myhr KM (2017) An update on cladribine for relapsing-remitting multiple sclerosis. Expert Opin Pharmacother 18(15):1627–1635.  https://doi.org/10.1080/14656566.2017.1372747 CrossRefPubMedGoogle Scholar
  40. Isakovic A, Harhaji L, Dacevic M, Trajkovic V (2008) Adenosine rescues glioma cells from cytokine-induced death by interfering with the signalling network involved in nitric oxide production. Eur J Pharmacol 591:106–113.  https://doi.org/10.1016/j.ejphar.2008.06.076 CrossRefPubMedGoogle Scholar
  41. Jacobson KA (1998) Adenosine A3 receptors: novel ligands and paradoxical effects. Trends Pharmacol Sci 19:184–191.  https://doi.org/10.1016/S0165-6147(98)01203-6 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Jacobson KA, Tosh DK, Jain S, Gao ZG (2019) Historical and current adenosine receptor agonists in preclinical and clinical development. Front Cell Neurosci 13:124.  https://doi.org/10.3389/fncel.2019.00124 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kelly GL, Strasser A (2011) The essential role of evasion from cell death in cancer. Adv Cancer Res 111:39–96.  https://doi.org/10.1016/B978-0-12-385524-4.00002-7 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Kreitman RJ, Arons E (2018) Update on hairy cell leukemia. Clin Adv Hematol Oncol 16(3):205–215PubMedPubMedCentralGoogle Scholar
  45. Lazarowski ER, Sesma JI, Seminario-Vidal L, Kreda SM (2011) Molecular mechanisms of purine and pyrimidine nucleotide release. Adv Pharmacol 61:221–261.  https://doi.org/10.1016/B978-0-12-385526-8.00008-4 CrossRefPubMedGoogle Scholar
  46. Lee JK, Won JS, Singh AK, Singh I (2005) Adenosine kinase inhibitor attenuates the expression of inducible nitric oxide synthase in glial cells. Neuropharmacology 48:151–160.  https://doi.org/10.1016/j.neuropharm.2004.09.006 CrossRefPubMedGoogle Scholar
  47. Liliemark J (1997) The clinical pharmacokinetics of cladribine. Clin Pharmacokinet 32:120–131.  https://doi.org/10.2165/00003088-199732020-00003 CrossRefPubMedGoogle Scholar
  48. Melani A, De Micheli E, Pinna G, Alfieri A, Corte LD, Pedata F (2003) Adenosine extracellular levels in human brain gliomas: an intraoperative microdialysis study. Neurosci Lett 346:93–96.  https://doi.org/10.1016/S0304-3940(03)00596-2 CrossRefPubMedGoogle Scholar
  49. Melani A, Corti F, Stephan H, Müller CE, Donati C, Bruni P, Vannucchi MG, Pedata F (2012) Ecto-ATPase inhibition: ATP and adenosine release under physiological and ischemic in vivo conditions in the rat striatum. Exp Neurol 233(1):193–204.  https://doi.org/10.1016/j.expneurol.2011.09.036 CrossRefPubMedGoogle Scholar
  50. Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Borea PA (2006) Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol 72:19–31.  https://doi.org/10.1016/j.bcp.2006.03.020 CrossRefPubMedGoogle Scholar
  51. Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi PG, Borea PA (2007) Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol 72:162–172.  https://doi.org/10.1124/mol.106.031849 CrossRefPubMedGoogle Scholar
  52. Morrone FB, Jacques-Silva MC, Horn AP, Bernardi A, Schwartsmann G, Rodnight R, Lenz G (2003) Extracellular nucleotides and nucleosides induce proliferation and increase nucleoside transport in human glioma cell lines. J Neuro-Oncol 64:211–208CrossRefGoogle Scholar
  53. Nazario LR, da Silva RS, Bonan CD (2017) Targeting adenosine signaling in Parkinson’s disease: from pharmacological to non-pharmacological approaches. Front Neurosci 11:6–58.  https://doi.org/10.3389/fnins.2017.00658 CrossRefGoogle Scholar
  54. Nomura Y, Inanami O, Takahashi K, Matsuda A, Kuwabara M (2000) 2-Chloro-2′-deoxyadenosine induces apoptosis through the Fas/Fas ligand pathway in human leukemia cell line MOLT-4. Leukemia 14:299–306CrossRefGoogle Scholar
  55. Ohkubo S, Nagata K, Nakahata N (2007) Adenosine uptake-dependent C6 cell growth inhibition. Eur J Pharmacol 577:35–43.  https://doi.org/10.1016/j.ejphar.2007.08.025 CrossRefPubMedGoogle Scholar
  56. Palmer TM, Stiles GL (2000) Identification of threonine residues controlling the agonist-dependent phosphorylation and desensitization of the rat A(3) adenosine receptor. Mol Pharmacol 57:539–545.  https://doi.org/10.1124/mol.57.3.539 CrossRefPubMedGoogle Scholar
  57. Pardridge WM, Yoshikawa T, Kang YS, Miller LP (1994) Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs. J Pharmacol Exp Ther 268:14–18PubMedGoogle Scholar
  58. Pastor-Anglada M, Pérez-Torras S (2018) Who is who in adenosine transport. Front Pharmacol 9:627.  https://doi.org/10.3389/fphar.2018.00627 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Rajkumar SV, Burch PA, Nair S, Dinapoli RP, Scheithauer B, O’Fallon JR, Etzell PS, Leitch JM, Morton RF, Marks RS (1999) Phase II north central Cancer treatment group study of 2-chlorodeoxyadenosine in patients with recurrent glioma. Am J Clin Oncol 22:168–171CrossRefGoogle Scholar
  60. Sands WA, Martin AF, Strong EW, Palmer TM (2004) Specific inhibition of nuclear factor-kappaB-dependent inflammatory responses by cell type-specific mechanisms upon A2A adenosine receptor gene transfer. Mol Pharmacol 66:1147–1159.  https://doi.org/10.1124/mol.104.001107 CrossRefPubMedGoogle Scholar
  61. Schulte G, Fredholm BB (2003) Signaling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 5(9):813–827.  https://doi.org/10.1016/S0898-6568(03)00058-5 CrossRefGoogle Scholar
  62. Sek K, Mølck C, Stewart GD, Kats L, Darcy PK, Beavis PA (2018) Targeting adenosine receptor signalling in cancer immunotherapy. Int J Mol Sci 19(12):Pii: E3837.  https://doi.org/10.3390/ijms19123837 CrossRefGoogle Scholar
  63. Sinclair CJ, LaRivière CG, Young JD, Cass CE, Baldwin SA, Parkinson FE (2000) Purine uptake and release in rat C6 glioma cells: nucleoside transport and purine metabolism under ATP-depleting conditions. J Neurochem 75:1528–1538.  https://doi.org/10.1046/j.1471-4159.2000.0751528.x CrossRefPubMedGoogle Scholar
  64. Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF (2015) Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res 35(6):600–604.  https://doi.org/10.3109/10799893.2015.1030412 CrossRefPubMedGoogle Scholar
  65. Taliani S, La Motta C, Mugnaini L, Simorini F, Salerno S, Marini AM, Da Settimo F, Cosconati S, Cosimelli B, Greco G, Limongelli V, Marinelli L, Novellino E, Ciampi O, Daniele S, Trincavelli ML, Martini C (2010) Novel N2-substituted pyrazolo[3,4-d]pyrimidine adenosine A3 receptor antagonists: inhibition of A3-mediated human glioblastoma cell proliferation. J Med Chem 53:3954–3963.  https://doi.org/10.1021/jm901785w CrossRefPubMedGoogle Scholar
  66. Tomicic MT, Meise R, Aasland D, Berte N, Kitzinger R, Krämer OH, Kaina B, Christmann M (2015) Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget 6(32):33755–33768.  https://doi.org/10.18632/oncotarget.5274 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, Abbracchio MP, Jacobson KA, Cattabeni F, Martini C (2002) A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation. Mol Pharmacol 62:1373–1384.  https://doi.org/10.1124/mol.62.6.1373 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Trincavelli ML, Marroni M, Tuscano D, Ceruti S, Mazzola A, Mitro N, Abbracchio MP, Martini C (2004) Regulation of A2B adenosine receptor functioning by tumour necrosis factor a in human astroglial cells. J Neurochem 91:1180–1190.  https://doi.org/10.1111/j.1471-4159.2004.02793.x CrossRefPubMedGoogle Scholar
  69. Uribe D, Torres Á, Rocha JD, Niechi I, Oyarzún C, Sobrevia L, San Martín R, Quezada C (2017) Multidrug resistance in glioblastoma stem-like cells: role of the hypoxic microenvironment and adenosine signalling. Mol Asp Med 55:140–151.  https://doi.org/10.1016/j.mam.2017.01.009 CrossRefGoogle Scholar
  70. Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B (2011) CD73 has distinct roles in non hematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 121:2371–2382.  https://doi.org/10.1172/JCI45559 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Westphal M, Lamszus K (2011) The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci 12:495–508.  https://doi.org/10.1038/nrn3060 CrossRefPubMedGoogle Scholar
  72. Xu S, Shao QQ, Sun JT, Yang N, Xie Q, Wang DH, Huang QB, Huang B, Wang XY, Li XG, Qu X (2013) Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro-Oncology 15(9):1160–1172.  https://doi.org/10.1093/neuonc/not067 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological SciencesUniversity of Milan – Università degli Studi di MilanoMilanItaly

Personalised recommendations