Skip to main content
SpringerLink
Log in

Adenosine-induced cell death: evidence for receptor-mediated signalling

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Adenosine modulates the proliferation, survival and apoptosis of many different cell types, ranging from epithelial, endothelial and smooth muscle cells, to cells of the immune and neural lineages. In this review, we critically discuss the available in vitro and in vivo data which support a role for adenosine in both development-associated apoptosis, and in diseases characterized by either pathologically increased cell death (e.g., ischemia, trauma and aging-associated neurodegeneration) or abnormally reduced spontaneous apoptosis (e.g., cancer). Particular emphasis is given to the possible role of extracellular adenosine receptors, since these may represent novel and attractive molecular targets for the pharmacological modulation of apoptosis. In some instances, adenosine-induced cell death has been demonstrated to require entry of the nucleoside inside cells; however, in many other cases, activation of specific adenosine extracellular receptors has been demonstrated. Of the four G protein-coupled adenosine receptors so far identified, the A2A and the A3 receptors have been specifically implicated in modulation of cell death. For the A3 receptor, results obtained by exposing both cardiomyocytes and brain astrocytes to graded concentrations of selective agonists suggest induction of both cell protection and cell death. Such opposite effects, which likely depend on the degree of receptor activation, may have important therapeutic implications in the pharmacological modulation of cardiac and brain ischemia. For the A2A receptor, recent intriguing data suggest a specific role in immune cell death and immunosuppression, which may be relevant to both adenosine-deaminase-immunodeficiency syndrome (a pathology characterized by accumulation of adenosine to toxic levels) and in tumors where induction of apoptosis via activation of specific extracellular receptors may be desirable. Finally, preliminary data suggest that, in a similar way to the adenosine-deaminase-immunodeficiency syndrome, the abnormal accumulation of adenosine in degenerative muscular diseases may contribute to muscle cell death. Although the role of adenosine receptors in this effect still remains to be determined, these data suggest that adenosine-induced apoptosis may also represent a novel pathogenic pathway in muscular dystrophies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jacobson KA, von Lubitz DKJE, Daly JW, Fredholm BB. Adenosine receptor ligands: differences with acute and chronic treatment. Trends Pharmacol Sci 1996; 17: 108-113.

    Google Scholar 

  2. Jacobson KA, van Rhee AM. Development of selective purinoceptor agonists and antagonists. In: Jacobson KA, Jarvis MF, eds. Purinergic Approaches in Experimental Therapeutics. New York: Wiley, 1997: 101-128.

    Google Scholar 

  3. Knutsen LJS, Murray TF. Adenosine and ATP in epilepsy. In: Jacobson KA, Jarvis MF, eds. Purinergic Approaches in Experimental Therapeutics. New York: Wiley, 1997: 423-447.

    Google Scholar 

  4. von Lubitz DKJE, Lin R-CA, Beenhakker M, Boyd M, Bischofberger N, Jacobson KA. Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils. Eur J Pharmacol 1996; 316: 171-179.

    Google Scholar 

  5. Rudolphi KA, Schubert P. Purinergic interventions in traumatic and ischemic injury. In: Peterson PL, Phillis JW, eds. Novel Therapies for CNS Injuries. Rationales and Results. 1996: 327-346, CRC Press, Boca Raton, FL, USA.

    Google Scholar 

  6. Downey JM. Ischemic preconditioning. Nature's own cardioprotective intervention. Trends Cardiovasc Med 1992; 2: 170-176.

    Google Scholar 

  7. Belardinelli L, Curtis A, Bertolet B. Cardiac electrophysiology of adenosine: antiarrhythmic and proarrythmic actions. In: Jacobson KA, Jarvis MF, eds. Purinergic Approaches in Experimental Therapeutics. New York: Wiley, 1997: 185-202.

    Google Scholar 

  8. Jacobson KA, Kim HO, Siddiqi, SM, Olah ME, Stiles G, von Lubitz DKJE. A3 adenosine receptors: design of selective ligands and therapeutic prospects. Drugs of the Future 1995; 20: 689-699.

    Google Scholar 

  9. Jacobson MA, Chakravarty PK, Johnson RG, Norton R. Novel selective non-xanthine selective A3 adenosine receptor antagonists. Drug Devel Res 1996; 37: 131.

    Google Scholar 

  10. Jacobson KA, Moro S, Kim Y-C, Li AH. A3 adenosine receptors: protective vs. damaging effects identified using novel agonists and antagonists. Drug Devel Res 1998, 45: 113-124.

    Google Scholar 

  11. Kim Y-C, Ji Xd, Jacobson KA. Derivatives of the triazoloquinazoline adenosine antagonist (CGS15943) are selective for the human A3 receptor subtype. J Med Chem 1996; 39: 4142-4148.

    Google Scholar 

  12. Olsson RA. Adenosine receptors in the cardiovascular system. Drug Devel Res 1996; 39: 301-307.

    Google Scholar 

  13. Abbracchio MP, Rainaldi G, Giammarioli AM, et al. 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 1997; 241: 297-304.

    Google Scholar 

  14. Brambilla R, Cattabeni F, Ceruti S, et al. Activation of the human A3 adenosine receptor in CHO transfected cells results in cytosolic acidification and block of cells at the S phase. Drug Devel Res 1998; 43: 13.

    Google Scholar 

  15. Abbracchio MP. P1 and P2 receptors in cell growth and differentiation. Drug Devel Res 1996; 39: 393-406.

    Google Scholar 

  16. Kohno Y, Sei Y, Koshiba M, Kim HO, Jacobson KA. Induction of apoptosis in HL-60 human promyelocytic leukemia cells by selective adenosine A3 receptor agonists. Biochem Biophys Res Commun 1996; 219: 904-910.

    Google Scholar 

  17. Sei Y, von Lubitz DKJE, Abbracchio MP, Ji Xd, Jacobson KA. Adenosine A3 receptor agonist-induced neurotoxicity in rat cerebellar granule neurons. Drug Devel Res 1997; 40: 267-273.

    Google Scholar 

  18. Barbieri D, Abbracchio MP, Salvioli S, et al. Apoptosis by 2-chloro-2′-deoxy-adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells. Neurochem Int 1998; 32: 493-504.

    Google Scholar 

  19. Yao Y, Sei Y, Abbracchio MP, Kim Y-C, Jacobson KA. Adenosine A3 receptor agonists protect HL-60 and U-937 cells from apoptosis induced by A3 antagonists. Biochem Biophys Res Comm 1997; 232: 317-322.

    Google Scholar 

  20. Abbracchio MP, Ceruti S, Barbieri D, et al. A novel action for adenosine: apoptosis of astroglial cells in rat brain primary cultures. Biochem Biophys Res Comm 1995; 213: 908-915.

    Google Scholar 

  21. Ceruti S, Barbieri D, Franceschi C, et al. Dual actions of adenosine A3 receptor agonists on mammalian astrocytes: protection at low concentrations and apoptosis at high concentrations. Drug Devel Res 1996; 37: 177.

    Google Scholar 

  22. Szondy Z. Adenosine stimulates DNA fragmentation in human thymocytes by Ca2+-mediated mechanisms. Biochem J 1994; 304: 877-885.

    Google Scholar 

  23. Szondy Z. The 2-chlorodeoxyadenosine-induced cell death signalling pathway in human thymocytes is different from that induced by 2-chloroadenosine. Biochem J 1995; 311: 585-588.

    Google Scholar 

  24. Schubert P, Ogata TI, Marchini C, Ferroni S, Rudolphi K. Protective mechanisms of adenosine in neurons and glial cells. Ann N Y Acad Sci 1997; 825: 1-10.

    Google Scholar 

  25. Kohno Y, Ji X-d, Mawhorter SD, et al. Activation of adenosine A3 receptor on human eosinophils raises intracellular Ca2+ and induces apoptosis. Drug Devel Res 1996; 37: 182.

    Google Scholar 

  26. Abbracchio MP, Saffrey MJ, Hopker V, Burnstock G. Modulation of astroglial cell proliferation by analogues of adenosine and ATP in primary cultures of rat striatum. Neurosci 1994; 59: 67-76.

    Google Scholar 

  27. Abbracchio MP, Ceruti S, Brambilla R, et al. Adenosine A3 receptors and viability of astrocytes. Drug Devel Res 1998; 45: 378-386.

    Google Scholar 

  28. Shneyvais V, Nawrath H, Jacobson KA, Shainberg A. Induction of apoptosis in cardiac myocytes by an A3 adenosine receptor agonist. Exp Cell Res 243: 383-397.

  29. Rufini S, Rainaldi G, Abbracchio MP, Fiorentini C, Franceschi C, Malorni W. Adenosine-induced apoptosis of C2C12 myoblastic cells. Basic Appl Myol 1997; 7: 395-397.

    Google Scholar 

  30. Rufini S, Rainaldi G, Abbracchio MP, et al. Actin cytoskeleton as a target for 2-chloro-adenosine: evidence for induction of apoptosis in C2C12 myoblastic cells. Biochem Biophys Res Comm 1997; 238: 361-366.

    Google Scholar 

  31. Strickler J, Jacobson KA, Liang BT. Direct preconditioning of cultured chick ventricular myocytes. Novel functions of cardiac A2A and A3 receptors. J Clin Invest 1996; 98: 1773-1779.

    Google Scholar 

  32. Liang BT, Jacobson KA. A physiological role of the adenosine A3 receptor: sustained cardioprotection. Proc Natl Acad Sci USA 1998; 95: 6995-6999.

    Google Scholar 

  33. Stambaugh K, Jacobson KA, Jiang J-I, Liang, BT. A novel cardioprotective function of adenosine A1 and A3 receptors during prolonged stimulated ischemia. Am J Physiol 1997; 273: H501-H505.

    Google Scholar 

  34. Brown R. The bcl-2 family of proteins. Br Med Bull 1997; 53: 466-477.

    Google Scholar 

  35. Chen DF, Schneider GE, Martinou J-C, Tonegawa S. Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 1997; 385: 434-439.

    Google Scholar 

  36. Burridge K, Chrzanowska-Wodnicka M. Focal adhesion, contractility and signaling. Ann. Rev Cell Develop Biol 1996; 12: 463-518.

    Google Scholar 

  37. Wakade TD, Palmer KC, McCauley R, Przywara DA, Wakade AR. Adenosine-induced apoptosis in chick embryonic sympathethic neurons: a new physiological role for adenosine. J Physiol 1995; 488: 123-128.

    Google Scholar 

  38. Tanaka Y, Yoshihara K, Tsuyuki M, Kamiya T. Apoptosis induced by adenosine in human leukemia HL-60 cells. Exp Cell Res 1994; 213: 242-252.

    Google Scholar 

  39. Ruchaud S, Zorn M, Davilar-Villar E, et al. Evidence for several pathways of biological response to hydrolysable cAMP analogues using a model system of apoptosis in IPC-81 leukaemia cells. Cell Pharmacol 1995; 2: 127-140.

    Google Scholar 

  40. Hoffmann C, Raffel S, Ruchaud S, et al. Chloro-substituted cAMP analogues and their adenosine metabolites induce apoptosis of the human promelocytic leukemia cell line NB4: molecular basis for cell type selectivity. Cell Pharmacol 1996; 3: 417-427.

    Google Scholar 

  41. Hoffmann C. Nucleotid-Analoge als molekulare Sonden zur Aufklärung von Mechanismen der Zellteilung, Differenzierung und der Apoptosis Dissertation, Universität Bremen, 1996.

  42. Vintermyr OK, Bøe R, Brustugun OT, Maronde E, Aakvaag A, Døskeland SO. Cyclic Adenosine Monophosphate (cAMP) Analogs 8-Cl-and 8-NH2-cAMP Induced Cell Death Independently of cAMP Kinase-Mediated Inhibition of the G1/S Transition in Mammary Carcinoma Cells (MCF-7). Endocrinology 1995; 136: 2513-2520.

    Google Scholar 

  43. Porter AG, Ng P, Jänicke RU. Death substrates come alive BioAssay, 1997; 19: 501-507.

    Google Scholar 

  44. Ceruti S, Barbieri D, Veronese E, et al. Different pathways of apoptosis revealed by 2-chloro-adenosine and deoxy-D-ribose in mammalian astroglial cells. J Neurosci Res 1997; 47: 372-383.

    Google Scholar 

  45. Endresen PC, Eide TJ, Aarbakke J. Cell death initiated by 3-deazaadenosine in HL-60 cells is apoptosis and is partially inhibited by homocysteine. Biochem Pharmacol 1993; 46: 1893-1901.

    Google Scholar 

  46. Wakade AR, Przywara A, Palmer KC, Kulkarni JS, Wakade TD. Deoxynucleoside Induces Neuronal Apoptosis Independent of Neurotrophic Factors. J Biol Chem 1995; 270: 17986-17992.

    Google Scholar 

  47. Ceruti S, Franceschi C, Barbieri D, et al. A reappraisal for the use of cladribine (2-chloro-2′-deoxy-adenosine) in human cancer: a study on its mechanism of action in astrocytoma cells. Cancer Res, submitted for publication.

  48. Knutsen T, Elmer WA. Evidence for negative control of growth by adenosine in the mammalian embryo: induction of Hmx/+ mutant limb outgrowth by adenosine deaminase. Differentiation 1987; 33: 270-279.

    Google Scholar 

  49. Petrungaro S, Salustri A, Siracusa G. Adenosine potentiates the delaying effect of dbcAMP on meiosis resumption in denuded mouse oocytes. Cell Biol Int Rep 1986; 10: 993.

    Google Scholar 

  50. Crossland WJ, Kulkarni J, Wakade AR. The effects of adenosine and 2-deoxyadenosine on chick embryo sympathetic ganglion cells in vivo. Neurosci Abstr 1996; 22, part 1: 27.10.

  51. von Lubitz DKJE, Lin RCS, Popik P, Carter MF, Jacobson KA. Adenosine A3 receptor stimulation and cerebral ischemia. Eur J Pharmacol 1994; 263: 59-67.

    Google Scholar 

  52. Dunwiddie TV, Diao L, Kim HO, Jiang J-l, Jacobson KA. Activation of hippocampal adenosine A3 receptors produces a heterologous desensitization of A1 receptor mediated responses in rat hippocampus. J Neurosci 17: 607-614.

  53. Macek TA, Schaffhauser H, Conn PJ. Protein Kinase C and A3 adenosine receptor activation inhibit presynaptic metabotropic glutamate receptor (mGluR) function and uncouple mGluRs from GTP-binding proteins. J Neurosci 1998; 18: 6138-6146.

    Google Scholar 

  54. Kitagawa K, Matsumoto M, Tagaya M, et al. 'Ischemic tolerance' phenomenon found in the brain. Brain Res 1990; 528: 21-24.

    Google Scholar 

  55. Monopoli A, Lozza G, Forlani A, Mattavelli A, Ongini E. Blockade of A2A adenosine receptors by SCH 58261 results in neuroprotective effects in cerebral ischemia in rats. Neuroreport 1998; in press.

  56. Phillis JW, O'Regan MHO. Prevention of ischemic brain injury by adenosine receptor activation. Drug Develop Res 1993; 28: 390-394.

    Google Scholar 

  57. Ongini E, Schubert P. Neuroprotection induced by stimulating A1 or blocking A2A adenosine receptors: an apparent paradox. Drug Devel Res 1998; 45: 387-393.

    Google Scholar 

  58. Garcia-Martinez V, Macias D, Ganan Y, et al. Internucleosomal DNA fragmentation and programmed cell death (apoptosis) in the interdigital tissue of the embryonic chick leg bud. J Cell Sci 1993; 106: 201-208.

    Google Scholar 

  59. Schwartz LM. Insect muscle as a model for programmed cell death. J Neurobiol 1992; 23: 1312-1326.

    Google Scholar 

  60. Tidball JG, Albrecht DE, Lokensgard BE, Spencer MJ. Apoptosis precedes necrosis of dystrophin-deficient muscle. J Cell Sci 1995; 108: 2197-2204.

    Google Scholar 

  61. Fidzianska A, Goebel HH, Warlo I. Acute infantile spinal muscular atrophy. Muscle apoptosis as a proposed pathogenetic mechanism. Brain 1990; 113: 433-445.

    Google Scholar 

  62. Sandri M, Carraro U, Podhorska-Okolow M, et al. Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exercise. FEBS Letters 1995; 373: 291-295.

    Google Scholar 

  63. Castro-Gago M, Lojo S, Novo I, del Rio R, Pena J, Rodriguez-Segade S. Effects of chronic allopurinol therapy on purine metabolism in Duchenne muscular dystrophy. Biochem Biophys Res Commun 1987; 147: 152-157.

    Google Scholar 

  64. Camina F, Novo-Rodriguez MI, Rodriguez-Segade S, Castro-Gago M. Purine and carnitine metabolism in muscle of patients with Duchenne muscular dystrophy. Chim Clin Acta 1995; 243: 151-164.

    Google Scholar 

  65. Cohen A, Hirschhorn R, Horowitz SD, et al. Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci USA 1978; 75: 471-476.

    Google Scholar 

  66. Huang S, Apasov S, Koshiba M, Sitkovski M. Role of A2A extracellular adenosine receptor-mediated inhibition of T-cell activation and expansion. Blood 1997; 90: 1600-1610.

    Google Scholar 

  67. Koshiba M, Kojima H, Huang S, Apasov S, Sitkovsky MV. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J Biol Chem 1997; 272: 25881-25889.

    Google Scholar 

  68. Apasov SG, Koshiba M, Chused TM, Sitkovski, MV. Effects of extracellular ATP and adenosine on different thymocyte subsets. Possible role of ATP-gated channels and G-protein-coupled purinergic receptors. The Journal of Immunology 1997; 158: 5095-5105.

    Google Scholar 

  69. Kizaki H, Suzuki K, Tadakuma T, Ishimura Y. Adenosine receptor-mediated accumulation of cyclic AMP-induced T lymphocyte death through intranucleosomal DNA cleavage. J Biol Chem 1990; 265: 5280-5284.

    Google Scholar 

  70. Bryson HM, Sorkin EM. Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies. Drugs 1993; 46: 872-894.

    Google Scholar 

  71. Beutler E. Cladribine (2-chlorodeoxyadenosine). The Lancet 1992; 340: 952-956.

    Google Scholar 

  72. Wood AJJ. New purines analogues for the treatment of hairy-cell leukemia. N Engl J Med 1994; 330: 691-697.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland, 20892, USA

    K. A. Jacobson & C. Hoffmann

  2. Institute of Pharmacological Sciences, School of Pharmacy, University of Milan, via Balzaretti 9, 20133, Milan, Italy

    F. Cattabeni & M. P. Abbracchio

Authors
  1. K. A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Cattabeni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. P. Abbracchio
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacobson, K.A., Hoffmann, C., Cattabeni, F. et al. Adenosine-induced cell death: evidence for receptor-mediated signalling. Apoptosis 4, 197–211 (1999). https://doi.org/10.1023/A:1009666707307

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009666707307

Search

Navigation