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

Abstract

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-beta-D-ribofuranonamide (Cl-IB-MECA), on apoptosis in two human leukemia cell lines, HL-60 and MOLT-4, were investigated. Cl-IB-MECA (> or =30 microM) 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 48hr 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)[1,2,4]triazolo[1,5-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)AR-mediated 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-MECA-induced 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.

• Authors: Seong Gon Kim, Gnana Ravi, Carsten Hoffmann, Yun Jin Jung, Min Kim, Aishe Chen, Kenneth A Jacobson
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 63 Issue 5 Pg. 871-80 (Mar 01 2002) ISSN: 0006-2952 [Print] England
• PMID: 11911839 (Publication Type: Journal Article)

Chemical References

• Antibodies
• Purinergic P1 Receptor Antagonists
• Receptor, Adenosine A3
• Tumor Suppressor Protein p53
• fas Receptor
• Type C Phospholipases
• Adenosine
• Calcium
• 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Antibodies (pharmacology)
• Apoptosis
• Blotting, Western
• Calcium (metabolism)
• Drug Interactions
• HL-60 Cells
• Humans
• Leukemia (pathology)
• Purinergic P1 Receptor Antagonists
• Receptor, Adenosine A3
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (metabolism)
• Type C Phospholipases (metabolism)
• fas Receptor (biosynthesis, immunology)