Adenosine A3Receptor Agonists Protect HL-60 and U-937 Cells from Apoptosis Induced by A3Antagonists

Yao, Yao; Sei, Yoshitatsu; Abbracchio, Maria P.; Jiang, Jinling; Kim, Yong-Chul

doi:10.1006/bbrc.1997.6290

Cited by 95 publications

(77 citation statements)

References 15 publications

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“…M) protected against apoptosis whereas high concentrations ( G 10 ? M) caused apoptosis [29]. The same differential effect of adenosine was seen in human EC [30].…”

Section: Discussionsupporting

confidence: 53%

Endothelial cell cytoprotection induced in vitro by allo‐ or xenoreactive antibodies is mediated by signaling through adenosine A2 receptors

et al. 2003

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Endothelial cell (EC) expression of proteins such as hemoxygenase-1 or Bcl-xL is associated with enhanced survival of vascularized allo-or xenografts. These grafts are resistant to humoral rejection, a phenomenon called accommodation. In vitro, low concentrations of allo-and xenoreactive antibody (XNA) induce a cytoprotective phenotype in EC similar to that seen in accommodated grafts. In this study we examine whether adenosine plays a role in antibody-induced cytoprotection. Porcine EC were incubated with human anti-pig XNA or specific alloantibody. EC expressed Bcl-xL and were protected from TNF-mediated apoptosis. Bcl-xL expression was inhibited by an adenosine A2 receptor antagonist. Human antipig XNA were shown to bind and induce cyclic adenosine 3',5'-monophosphate (cAMP) generation through these receptors. This activity was abolished by depletion of antigal § (1-3)gal-specific XNA. In contrast, alloantibody caused adenosine production. Protection from TNF-mediated apoptosis was also mediated through A2 receptor but involved additional non-cAMP-dependent signaling. This study indicates a molecular mechanism common to both antibody-mediated cytoprotection and ischemic preconditioning and suggests a potential therapeutic avenue based on adenosine for improving the outcome of transplanted grafts in those patients with pre-existing anti-graft antibody.

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“…M) protected against apoptosis whereas high concentrations ( G 10 ? M) caused apoptosis [29]. The same differential effect of adenosine was seen in human EC [30].…”

Section: Discussionsupporting

confidence: 53%

Endothelial cell cytoprotection induced in vitro by allo‐ or xenoreactive antibodies is mediated by signaling through adenosine A2 receptors

et al. 2003

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“…Clarification of the need for such high doses of agonists, thousands of times higher than the K i values at A 3 receptors, has awaited the introduction of selective A 3 receptor antagonists, which are now available for the human A 3 receptor. As discussed above, A 3 receptor antagonists of diverse structures alone cause apoptotic cell death 39 , and cells may be rescued by subcytotoxic concentrations of selective A 3 receptor agonists.…”

Section: The Immune System and Inflammationmentioning

confidence: 95%

“…Nanomolar concentrations of selective agonists tend to protect cells, while micromolar concentrations are often toxic (Table 1) 24 . In certain cultured cell lines, antagonists alone are toxic 39 . The fact that A 3 receptor antagonists representing three diverse chemical classes evoked the common biological effect of apoptosis (programmed cell death, see below) suggests that a tonic state of activation of the A 3 receptor might exist, and that this possible low level of receptor activation has a protective role.…”

Section: Protective Versus Lethal Effects Of a 3 Receptor Activationmentioning

confidence: 99%

“…Apoptosis, with characteristic DNA fragmentation, has been shown to occur in human leukaemia HL-60 cells, MCF-7 breast cancer cells and in human peripheral blood eosinophils in response to high concentrations (≥10 μM) of A 3 receptorselective agonists 24,39 . A mediator of apoptosis, bak (pro-apoptotic Bcl-2 homology protein), is upregulated under these conditions 39 . The protective effects of A 3 receptor activation might involve cytokines.…”

Section: The Immune System and Inflammationmentioning

confidence: 99%

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Adenosine A3 receptors: novel ligands and paradoxical effects

Jacobson

1998

Trends in Pharmacological Sciences

283

270

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The physiological role of the adenosine A 3 receptor is being investigated using newly synthesized, selective ligands. Recently, in addition to agonists, selective antagonists have been developed that belong to three distinct, non-purine chemical classes: flavonoids, 1,4-dihydropyridine derivatives (e.g. MRS1191, which is 1300-fold selective for human adenosine A 3 vs A 1 /A 2A receptors, with a K i value of 31 nM) and the triazoloquinazolines (e.g. MRS1220, which has a K i value of 0.65 nM). The A 3 receptor has proven enigmatic in terms of antagonist ligand specificity, coupling to second messengers, and biological effects in the CNS, inflammatory system and cardiovascular system. A 3 receptors are also potentially involved in apoptosis. It appears that intense, acute activation of A 3 receptors acts as a lethal input to cells, while low concentrations of A 3 receptor agonists protect against apoptosis. Here, Kenneth Jacobson describes how A 3 receptor agonists might be useful in treating inflammatory conditions, possibly through their inhibition of tumour necrosis factor α (TNF-α) release, which has been shown in macrophages. A 3 receptor antagonists might be useful in treating asthma or acute brain ischaemia. Recently, the versatility of A 3 receptor agonists, administered either before or during ischaemia, in eliciting potent cardioprotection has been shown.Adenosine has been shown to be a critical modulator of a vast array of physiological functions, through activation of one or more of the four known receptor subtypes: A 1 , A 2A , A 2B and A 3 (Refs 1, 2). The adenosine A 1 and A 2A receptors, pharmacologically well characterized through the use of selective ligands, generally have a protective role, i.e. in decreasing energy demand and increasing energy supply, respectively, under conditions of stress. Relatively recently identified through cloning 1,2 , the A 3 receptor (Fig. 1) has provided a new challenge to medicinal chemists in search of selective ligands 3 and to pharmacologists in defining its role in vivo. With the recent availability of selective agonists and antagonists, both protective and lethal effects of A 3 receptor activation have been discovered.In humans, A 3 receptors are found in the lungs, liver, heart and kidneys, with a lower density being found in the brain and testes 2 . A 3 receptors are found in both neurones 4 and astrocytes 5 . Although the density of A 3 receptors in the brain is possibly too low for mapping using either autoradiography with a high-affinity agonist, [ 125 I]N 6 -(4-aminobenzyl)-adenosine-5′-N-methyluronamide {[ 125 I]I-AB-MECA} (Fig. 2) 6,7 , or in situ hybridization 8 , a role for this subtype in the CNS has been proposed 9,10 .The A 3 receptors are under scrutiny in relation to potential therapeutic approaches for treating inflammatory and neurodegenerative diseases, asthma and cardiac ischaemia [10][11][12][13][14][15][16][17] . A 3 receptor ligands are protective in cerebral ischaemia models in gerbils 10 . In the heart, both A 1 and A 3 recepto...

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“…Following the introduction of A 3 AR-selective ligands [1][2][3], the A 3 AR has been demonstrated to have diverse physiological functions, including its effects on inflammation [4], hypotension [5], mast cell degradation [6], protection of brain and heart [7][8][9], and apoptosis [10][11][12][13][14][15]. Specifically, potent A 3 AR agonists showed dual effects leading to either cellular protection or death.…”

Section: Introductionmentioning

confidence: 99%

p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA

Kim

Ravi

Hoffmann

et al. 2002

Biochemical Pharmacology

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A 3 adenosine receptor (A 3 AR) agonists have been reported to influence cell death and survival. The effects of an A 3 AR agonist, 1- [2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-β-D-ribofuranonamide (Cl-IB-MECA), on apoptosis in two human leukemia cell lines, HL-60 and MOLT-4, were investigated. Cl-IB-MECA (≥30 μM) increased the apoptotic fractions, as determined using fluorescence-activated cell sorting (FACS) analysis, and activated caspase 3 and poly-ADP-ribose-polymerase. Known messengers coupled to A 3 AR (phospholipase C and intracellular calcium) did not seem to play a role in the induction of apoptosis. Neither dantrolene nor BAPTA-AM affected the Cl-IB-MECA-induced apoptosis. Cl-IB-MECA failed to activate phospholipase C in HL-60 cells, while UTP activated it through endogenous P2Y 2 receptors. Induction of apoptosis during a 48 hr exposure to Cl-IB-MECA was not prevented by the A 3 AR antagonists [5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] (MRS 1220) or N- [9-chloro-2-(2-furanyl) [l,2,4]triazolo [l,5-c]quinazolin-5-yl]benzeneacetamide (MRS 1523). Furthermore, higher concentrations of MRS 1220, which would also antagonize A 1 and A 2A receptors, were ineffective in preventing the apoptosis. Although Cl-IB-MECA has been shown in other systems to cause apoptosis through an A 3 ARmediated mechanism, in these cells it appeared to be an adenosine receptor-independent effect, which required prolonged incubation. In both HL-60 and MOLT-4 cells, Cl-IB-MECA induced the expression of Fas, a death receptor. This induction of Fas was not dependent upon p53, because p53 is not expressed in an active form in either HL-60 or MOLT-4 cells. Cl-IB-MECAinduced apoptosis in HL-60 cells was augmented by an agonistic Fas antibody, CH-11, and this increase was suppressed by the antagonistic anti-Fas antibody ZB-4. Therefore, Cl-IB-MECA induced apoptosis via a novel, p53-independent up-regulation of Fas. Published by Elsevier Science Inc.

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Adenosine A3Receptor Agonists Protect HL-60 and U-937 Cells from Apoptosis Induced by A3Antagonists

Cited by 95 publications

References 15 publications

Endothelial cell cytoprotection induced in vitro by allo‐ or xenoreactive antibodies is mediated by signaling through adenosine A2 receptors

Endothelial cell cytoprotection induced in vitro by allo‐ or xenoreactive antibodies is mediated by signaling through adenosine A2 receptors

Adenosine A3 receptors: novel ligands and paradoxical effects

p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA

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