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PMID: 11911839 Published · ppublish English Journal Article

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

Biochemical pharmacology ·Vol. 63 ·No. 5 ·2002-03-01 ·Pages 871-80

Kim SG, Ravi G, Hoffmann C, Jung YJ, Kim M, Chen A, Jacobson KA

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.

MeSH Terms
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
Chemicals
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
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kim Seong Gon
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Ravi Gnana
Hoffmann Carsten
Jung Yun Jin
Kim Min
Chen Aishe
Jacobson Kenneth A
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Article Info
Journal
Biochemical pharmacology
Abbr.
Biochem Pharmacol
ISSN
0006-2952
DOI
10.1016/s0006-2952(02)00839-0
Published
2002-03-01
Pages
871-80
Language
English
Region
England
NLM ID
0101032
PMCID
PMC4811183
Subset
IM
Grants
Intramural NIH HHS · Z01 DK031117-20 · United States
Intramural NIH HHS · Z99 DK999999 · United States
External Links
PubMed source DOI: 10.1016/s0006-2952(02)00839-0 PMC Full Text View journal details
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