Extracellular Cyclic AMP/Adenosine Signaling Pathway: A Potential Pharmacological Target for Therapeutic Intervention in Chronic Lymphocytic Leukemia
Received Date: Apr 05, 2017 / Accepted Date: Apr 08, 2017 / Published Date: Apr 10, 2017
The chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in adults of western countries with an estimated annual 15,000 new cases and 4,500 deaths in the USA [1,2]. CLL is a disorder characterized by a progressive accumulation of biologically and functionally incompetent lymphocytes. Clinically, CLL is a heterogeneous disease with variable prognosis depending on the age affected, being dependent on the presence of associated comorbidities, clinical stage and expression of molecular markers specific to the disease [3-6].
In tumor progression of CLL, numerous factors further the tumor growth, progression, invasiveness and dissemination. Among these factors, nucleosides (adenosine) and cyclic nucleotides (adenosine triphosphate) have capacity to bind in purinergic receptors and modulating not only tumor growth, and its capacity for dissemination, but also controlling the adaptive immune response [7-9].
Nucleotides like ATP can be converted to adenosine through the enzymes ectonucleotides, located on the surface of the plasma membrane [8-10]. The adenosine produced by the tumor cells, besides being used for the synthesis of nucleotides, can act as agonist of the purinergic receptor coupled to G protein (A1, A2a, A2b, A3), promoting the suppression of tumor infiltrating lymphocytes (immunosuppressive effect) and inflammatory activity (antiinflammatory effect) [8-12].
In the intracellular medium, cyclic AMP (cAMP) can act as a second messenger, with a relevant antitumoral activity by regulating cell differentiation, proliferation and apoptosis, as seen in different types of leukemia. Since the intracellular concentrations of cAMP are regulated by phosphodiesterases (PDE), the most studied being type 4 PDE (PDE4) [13-15]. In addition, the intracellular cAMP concentration in tumor cells can be regulated by the multidrug resistance protein 4 (MRP4), which acts as an efflux pump for cAMP to the extracellular medium, and subsequently degraded in adenosine by enzyme EctoPDE, located in outsider portion of plasma membrane .
The increase of extracellular adenosine turnover in the tumor microenvironment, as well as the increase in the amount of enzymes involved in this sequence of chemical reactions favor tumor growth, accompanied by the detriment of the antitumor activity by the immune system . Adenosine contributes to the survival of tumor cells by inhibiting the process of apoptosis-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and multiresistant drug phenotype of leukemic cells , with a high expression of catalytically active ectonucleotidases (such as CD73) being described in CLL . In addition, considering the existence of a cAMP efflux system mediated by multiresistant protein transporters: the blockade of adenosine receptors reduces the negative inotropic effect promoted by extracellular adenosine due to cAMP efflux system, altering important intracellular signaling pathways [20,21]. Thus, we have proposed that the pharmacological modulation of the intra and extracellular signaling mediated by cAMP and adenosine could be a new antitumoral strategy in CLL therapy [22-26].
Research supported by CNPq, FAPESP and CAPES.
- Bhattacharyya PK (2013) Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia. Indian J Pathol Microbiol 56:188-189.
- da Cunha-Bang C, Simonsen J, Rostgaard K, Geisler C, Hjalgrim H, et al. (2016) Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients. Blood Cancer J 6:e499.
- Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, et al. (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111: 5446-5456.
- Wierda WG, O'Brien S, Wang X, Faderl S, Ferrajoli A, et al. (2007) Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 109: 4679-4685.
- Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, et al. (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. New Engl J Med 343: 1910-1916.
- Bahlo J, Kutsch N, Bergmann M, Byrd J, Dohner H, et al. (2015) The International Prognostic Index for Patients with Chronic Lymphocytic Leukaemia (CLL-IPI) - an international meta-analysis. Hematol Oncol 33: 127-128.
- Di Virgilio F, Boeynaems JM, Robson SC (2009) Extracellular nucleotides as negative modulators of immunity. Curr Opin Pharmacol 9: 507-513.
- Burnstock G (2008) Unresolved issues and controversies in purinergic signalling. J Physiol (London) 586:3307-3312.
- Burnstock G, Verkhratsky A (2009) Evolutionary origins of the purinergic signalling system. Acta Physiol 195:415-447.
- Resta R, Yamashita Y, Thompson LF (1998) Ecto-enzyme and signaling functions of lymphocyte CD73. Immunol Rev 161:95–109.
- Haskó G, Cronstein BN (2004) Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25: 33-39.
- Sitkovsky MV, Ohta A (2005) The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol 26:299-304.
- Karin M (1994) Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors. Curr Opin Cell Biol 6: 415-424.
- Honma Y, Kasukabe T, Hozumi M (1978) Induction of lysozyme activity by adenosine 3′:5′-cyclic monophosphate in cultured mouse myeloid leukemia cells. Biochem. Biophys Res Commun 82: 1246-1250.
- Shayo C, Davio C, Brodsky A, Mladovan, A G, Legnazzi, BL, et al. (1997) Histamine modulates the expression of c-fos through cyclic AMP production via the H2 receptor in the human promonocytic cell line U937. Mol. Pharmacol 51: 983-990.
- Copsel S, Garcia C, Diez F, Vermeulem M, Baldi A, et al. (2011) Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem 286:6979-88.
- Ohta A (2016) A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol 7:109.
- Mikhailov A, Sokolovskaya A, Yegutkin GG, Amdahl H, West A, et al. (2008) CD73 participates in cellular multiresistance program and protects against TRAIL-induced apoptosis. J Immunol 181:464-475.
- Serra S, Horenstein AL, Vaisitti T, Brusa D, Rossi D, et al. (2011) CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood 118:6141-6152.
- Chiavegatti T, Costa VL Jr, Araújo MS, Godinho RO (2008) Skeletal muscle expresses the extracellular cyclic AMP-adenosine pathway. Br J Pharmacol 153: 1331-1340.
- Duarte T, Menezes-Rodrigues FS, Godinho RO (2012) Contribution of the extracellular cAMP-adenosine pathway to dual coupling of β2-adrenoceptors to Gs and Gi proteins in mouse skeletal muscle. J Pharmacol Exp Ther 341: 820-8.
- Caricati-Neto A, Garcia AG, Bergantin LB (2015) Pharmacological implications of the Ca2+/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. Pharmacol Res Perspect 3(5): e00181.
- Bergantin LB, Caricati-Neto A (2016) Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca2+/cAMP intracellular signalling interaction. Eur J Pharmacol 788: 255-260.
- Bergantin LB, Caricati-Neto A (2016) Novel Insights for Therapy of Parkinson’s disease: Pharmacological Modulation of the Ca2+/cAMP Signalling Interaction. Austin Neurol Neurosci 1: 1009.
- Bergantin LB, Caricati-Neto A (2016) Recent advances in pharmacotherapy of neurological and psychiatric disorders promoted by discovery of the role of Ca2+/cAMP signaling interaction in the neurotransmission and neuroprotection. Adv Pharmac J 1: 66-70.
- Errante PR, Caricati-Neto A, Bergantin LB (2017) Insights for the inhibition of cancer progression: Revisiting Ca2+ and cAMP signalling pathways. Adv Cancer Prev 2: e103.
Citation: Rodrigues FSM, Errante PR, Neto AC, Bergantin LB (2017) Extracellular Cyclic AMP/Adenosine Signaling Pathway: A Potential Pharmacological Target for Therapeutic Intervention in Chronic Lymphocytic Leukemia. Adv Cancer Prev 2: e104. Doi: 10.4172/2472-0429.1000e104
Copyright: © 2017 Rodrigues FSM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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