Agmatine inhibits the proliferation of rat hepatoma cells by modulation of polyamine metabolism

Gardini, Giulia; Cravanzola, Carlo; Autelli, Riccardo; Testore, Giovanni; Cesa, Roberta; Morando, Laura; Solinas, Sandro P.; Muzio, Giuliana; Grillo, M.A.; Colombatto, Sebastiano

doi:10.1016/s0168-8278(03)00386-6

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…The relation between these effects and the decrease of intracellular polyamine content are in agreement with previous reports on many other cell lines (Satriano et al 2001b;Gardini et al 2003;Molderings et al 2004). Furthermore, human MC stimulated to increase their proliferative kinetics are significantly more sensitive to the antiproliferative effects of agmatine than normally cultured cells.…”

Section: Discussionsupporting

confidence: 92%

“…Agmatine administration also reduces total intracellular polyamine content, most notably of putrescine and spermidine. The marked declines of putrescine and spermidine, but not spermine, are in agreement with the agmatine results in rat liver hepatoma cell line (Gardini et al 2003) and MCT cells (Satriano et al 1998), and with selective inhibition of ODC activity with difluoromethylornithine (DFMO) in a murine B cell line (Nitta et al 2002). Administration of putrescine completely eradicates the antiproliferative effects of agmatine (Fig.…”

Section: Discussionsupporting

confidence: 85%

“…Since agmatine is an endogenous molecule, it may be expected to show a low risk of adverse effects. Previous experiments have shown that the antiproliferative effects of agmatine are due, in large part, to modulation of polyamine metabolism (Satriano et al 1998;Gardini et al 2003;Molderings et al 2004). In rat liver hepatoma cells, the antiproliferative effects of agmatine are concentration dependent.…”

Section: Discussionmentioning

confidence: 99%

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Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

Eto

Isome

Sano

et al. 2006

Tohoku J. Exp. Med.

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Polyamines play an essential role in the growth and differentiation of mammalian cells. The depletion of intracellular polyamines results in the suppression of growth. Proliferation of glomerular mesangial cells (MC) is the most common pathologic change in many forms of glomerulonephritis. Agmatine is a metabolite of arginine via arginine decarboxylase (ADC), highly expressed in the kidney, and unique in its capacity to suppress intracellular polyamine levels required for proliferation. As agmatine enters mammalian cells via the polyamine transport system, its antiproliferative effects may preferentially target cells with increased proliferative kinetics. In the present study, we evaluated the antiproliferative effects of agmatine on human MC in vitro. MC proliferation was stimulated with 20% fetal bovine serum (FBS) or platelet-derived growth factor (PDGF-BB, 20 ng/ml). Cell proliferation was measured using the (4.3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) proliferation assay. Intracellular polyamine levels were assayed by high performance liquid chromatography, and cell death was assessed by cellular DNA fragmentation enzyme-linked immunosorbent assay. The MTT proliferation assay showed that agmatine significantly suppressed proliferation of human MC treated with 20% FBS or 5% FBS + PDGF as compared to human MC treated with 5% FBS. Polyamine levels were markedly lower in cells treated with agmatine, and proliferation was rescued by administration of putrescine. The fragmented DNA was hardly detected in agmatine-treated human MC. In summary, human MC stimulated to increase their proliferative kinetics are significantly more sensitive to the antiproliferative effects of agmatine than normally cultured cells. Suppressed proliferation of the agmatine-treated human MC is not due to increased cell death. These results suggest that agmatine is a promising drug candidate for the treatment of human mesangial proliferative glomerulonephritis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

Eto

Isome

Sano

et al. 2006

Tohoku J. Exp. Med.

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“…Moreover, HTC (rat liver hepatoma derived from Morris hepatoma) cells treated with agmatine showed a progressive accumulation of cells in G 2 /M phase of the cell cycle with no evident signs of apoptosis or necrosis (Gardini et al, 2003). Against this background, it is tempting to speculate that Az-mediated Aurora-A degradation might be one of the multiple functions of Az on cell growth.…”

Section: Antizyme1-dependent Aurora-a Degradation Sk Lim and G Gopalanmentioning

confidence: 99%

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

Lim

Gopalan

2007

Oncogene

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“…The antiproliferative effects have garnered particular interest in the treatment of neoplasms, where levels of agmatine are lower than in the surrounding normal tissue (48). Agmatine suppresses growth through the reduction of intracellular polyamine levels, which are required for growth, and inhibition of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis, in all models studied to date (4,16,22,29,46,59,68). Reduction of cellular polyamine levels occurs by the induction of the polyamine autoregulatory protein antizyme (4,29,59), increasing activity of polyamine catabolism (16,68), and/or decreasing ODC activity by another mechanism, possibly by reduction of ODC translation (4,71).…”

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confidence: 99%

The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

Arndt¹,

Battaglia²,

Parisi³

et al. 2009

American Journal of Physiology-Cell Physiology

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Agmatine inhibits the proliferation of rat hepatoma cells by modulation of polyamine metabolism

Cited by 24 publications

References 25 publications

Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

Agmatine Suppresses Mesangial Cell Proliferation by Modulating Polyamine Metabolism

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

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