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GROWTH, DIFFERENTIATION, AND APOPTOSIS

The antiproliferative effects of agmatine correlate with the rate of cellular proliferation

¹Division of Nephrology-Hypertension and ⁴The Stein Institute for Research on Aging, Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System, La Jolla, California; ²Department of Genetics and Molecular Biology, School of Pharmacy, Musashino University, Nishi-Tokyo, Japan; and ³Department of Biochemistry II, The Jikei University School of Medicine, Tokyo, Japan

Submitted 25 February 2007 ; accepted in final form 29 April 2007

Polyamines are small cationic molecules required for cellular proliferation. Agmatine is a biogenic amine unique in its capacity to arrest proliferation in cell lines by depleting intracellular polyamine levels. We previously demonstrated that agmatine enters mammalian cells via the polyamine transport system. As polyamine transport is positively correlated with the rate of cellular proliferation, the current study examines the antiproliferative effects of agmatine on cells with varying proliferative kinetics. Herein, we evaluate agmatine transport, intracellular accumulation, and its effects on antizyme expression and cellular proliferation in nontransformed cell lines and their transformed variants. H-ras- and Src-transformed murine NIH/3T3 cells (Ras/3T3 and Src/3T3, respectively) that were exposed to exogenous agmatine exhibit increased uptake and intracellular accumulation relative to the parental NIH/3T3 cell line. Similar increases were obtained for human primary foreskin fibroblasts relative to a human fibrosarcoma cell line, HT1080. Agmatine increases expression of antizyme, a protein that inhibits polyamine biosynthesis and transport. Ras/3T3 and Src/3T3 cells demonstrated augmented increases in antizyme protein expression relative to NIH/3T3 in response to agmatine. All transformed cell lines were significantly more sensitive to the antiproliferative effects of agmatine than nontransformed lines. These effects were attenuated in the presence of exogenous polyamines or inhibitors of polyamine transport. In conclusion, the antiproliferative effects of agmatine preferentially target transformed cell lines due to the increased agmatine uptake exhibited by cells with short cycling times.

polyamines; antizyme; ornithine decarboxylase; polyamine transport

This article has been cited by other articles:

				M. A. Arndt, V. Battaglia, E. Parisi, M. J. Lortie, M. Isome, C. Baskerville, D. P. Pizzo, R. Ientile, S. Colombatto, A. Toninello, et al. The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1411 - C1419. [Abstract] [Full Text] [PDF]