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Agmatine inhibits growth via a cell cycle arrest and confers resistance to apoptosis
Author(s) -
Arndt Mary Ann,
Parisi Eva,
Isome Masato,
Satriano Joseph
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1238.25
Subject(s) - agmatine , apoptosis , cell cycle , cyclin d1 , cell cycle checkpoint , dna fragmentation , cyclin a , cyclin e , cell growth , cancer research , microbiology and biotechnology , cyclin b1 , chemistry , biology , programmed cell death , cyclin dependent kinase 1 , arginine , biochemistry , amino acid
The arginine metabolite agmatine suppresses growth. Notably, this effect preferentially targets cells with high proliferative kinetics (Isome, et al, AJP, 2007). However, the mechanisms of this process have yet to be defined. Here we demonstrate via FACS analysis a dose dependent G1 phase cell cycle arrest with agmatine administration. Western blot evaluations of G1 cell cycle proteins demonstrate decreases in cyclin D1 expression, phosphorylation state of the retinoblastoma protein, and cyclin A expression. We observe induction of cyclin kinase inhibitors p16 and p21, but not p53. Agmatine administered to cultured cells results in neither necrosis nor apoptosis, as shown by DNA fragmentation and chromatin condensation assays. Unexpectedly, agmatine decreases the expression and activity of caspase‐3 in a dose and time dependent fashion. Furthermore, agmatine inhibits the induction of caspase‐3 activity in response to apoptotic mediators, camptothecin and 5‐fluorouricil. CONCLUSIONS: Agmatine confers resistance to apoptosis and can suppress proliferation via a p53 independent cell cycle arrest. Aberrant apoptosis and/or proliferation are common pathologic complications. As previously shown in an in vivo model of glomerulonephritis (Ishizuka, JASN, 2000), agmatine may be a candidate for adjunctive therapy in renal disease. Funding: NIH/NIDDK, VA