Receptors responsive to extracellular uracil nucleotides

Communi, Didier; Robaye, Bernard; Janssens, Rodolphe; Parmentier, Marc; Boeynaems, Jean‐Marie

doi:10.1002/(sici)1098-2299(199811/12)45:3/4<130::aid-ddr7>3.0.co;2-t

Cited by 4 publications

(1 citation statement)

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“…When UTP was added to HL-60 cells, it increased the production of inositol phosphates in a concentrationdependent manner, demonstrating the existence of purinergic receptors coupled to PLC. However, MOLT-4 cells appear to lack P2Y 2 or P2Y 4 receptors, which are normally activated by UTP, although the presence of P2Y 6 receptors in MOLT-4 cells has been reported [25]. Therefore, Cl-IB-MECA did not act through a PLC-coupled A 3 AR.…”

Section: Discussionmentioning

confidence: 84%

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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Section: Discussionmentioning

confidence: 84%

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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Overview of P2Y receptors as therapeutic targets

Boeynaems¹,

Robaye²,

Janssens³

et al. 2001

Drug Development Research

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Currently the only P2Y receptor subtype targeted by drugs in clinical use is the P2T AC (or P2Y 12 ) receptor, which has been recently cloned and is only distantly related to other P2Y subtypes. It is believed that the active metabolites of thienopyridine antithrombotic agents (ticlopidine, clopidogrel) bind covalently to that receptor and inactivate it in an irreversible way. The same receptor is also the target of competitive antagonists derived from ATP, such as AR-C69931MX. Other subtypes also have potential as pharmacotherapeutic targets. The demonstration that P2Y 1 -/-mice have a defective platelet aggregation and increased resistance to thromboembolism suggests that P2Y 1 antagonists could constitute a new class of antithrombotic agents. Activation of the P2Y 2 receptor by aerosolized UTP and derivatives constitutes one strategy for the symptomatic treatment of cystic fibrosis and other obstructive airway diseases. The study of P2Y 2 -/-mice suggests that P2Y 4 and P2Y 6 receptors might constitute additional targets in that framework. P2Y 6 receptor antagonists might be useful in inflammatory bowel disease in view of their expression on activated T lymphocytes infiltrating the lesions in patients. The P2Y 11 receptor mediates the stimulatory effect of ATP on the granulocytic differentiation of HL-60 promyelocytic leukemia cells, suggesting that P2Y 11 agonists might be useful in the treatment of some forms of neutropenia and leukemia. Drug Dev.

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