Pharmacological characteristics of the specific transporter for the endogenous cell growth inhibitor agmatine in six tumor cell lines

Heinen, Anja; Brüss, Michael; Bönisch, Heinz; Göthert, M.; Molderings, Gerhard J.

doi:10.1007/s00384-002-0466-8

Cited by 14 publications

(16 citation statements)

References 33 publications

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“…3 To confirm that hOCT1, hOCT2 or hOCT3 are not involved in the specific agmatine transport, agmatine accumulation in three stably transfected HEK293 cell lines expressing either hOCT1, hOCT2 or hOCT3 were studied. 4 In non-transfected HEK293 cells, a specific agmatine uptake similar to that in the intestinal cell lines and in SK-MG-1 cells was present. However, expression of hOCT1 and hOCT3 in HEK293 cells did not further increase uptake of agmatine, 4 thus ruling out the transport of agmatine by those organic cation transporters.…”

Section: Pharmacological Characterization Of the Agmatine Uptake Processmentioning

confidence: 81%

“…2 In addition, we have recently demonstrated the existence of a specific carrier-mediated agmatine uptake in the human glioblastoma cell line SK-MG-1, 3 in six intestinal carcinoma cell lines and in HEK293 cells. 4 The detailed pharmacological characterization of the [ 14 C]agmatine uptake in SK-MG-1 and Caco-2 cells as representatives of tumor cells of different origin revealed that the agmatine carrier is not identical with the transporter for the structurally related amino acids arginine and lysine (system Y + ; SLC7A2), because neither L-arginine nor L-lysine affected [ 14 C]agmatine uptake (TABLE 1). Desipramine also had no effect on the uptake of [ 14 C]agmatine, indicating that the sodium-dependent norepinephrine transporter (SLC6A2) is not involved (TABLE 1).…”

Section: Pharmacological Characterization Of the Agmatine Uptake Processmentioning

confidence: 99%

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Identification and Pharmacological Characterization of a Specific Agmatine Transport System in Human Tumor Cell Lines

Molderings

Brüss

Bönisch

et al. 2003

Annals of the New York Academy of Sciences

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Specific accumulation of [(14C)]agmatine in six human intestinal tumor cell lines and in the glioma cell line SK-MG-1 was inhibited by phentolamine, idazoxan, clonidine, 1,3-di-(2-tolyl)guanidine, histamine, putrescine, spermine and spermidine. Corticosterone, desipramine, O-methylisoprenaline, cirazoline, moxonidine, l-arginine, l-lysine, verapamil, nifedipine, CdCl(2), ondansetron, and l-carnitine failed to inhibit specific [(14)C]agmatine accumulation, thus excluding that it is mediated by amino acid or monoamine carriers, by the putrescine carrier, by 5-HT(3) receptor channels, by Ca(2+) channels or by the organic cation transporters OCT1, OCT2, OCT3, OCTN1, or OCTN2. This conclusion is supported by the finding that transfection of HEK293 cells with cDNA encoding either hOCT1, hOCT2, or hOCT3 did not enhance specific [(14)C]agmatine accumulation compared to nontransfected cells. The data suggest that agmatine is accumulated by a specific agmatine transporter. Since incubation with exogenous agmatine for 24 hours increased intracellular agmatine content in all cell lines by a multiple of the basal endogenous content, the agmatine uptake system may be relevant for the regulation of the intra- and extracellular concentration of agmatine in humans.

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Section: Pharmacological Characterization Of the Agmatine Uptake Processmentioning

confidence: 81%

Section: Pharmacological Characterization Of the Agmatine Uptake Processmentioning

confidence: 99%

Identification and Pharmacological Characterization of a Specific Agmatine Transport System in Human Tumor Cell Lines

Molderings

Brüss

Bönisch

et al. 2003

Annals of the New York Academy of Sciences

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“…While agmatine influx transport has been demonstrated by rodent and human OCT2 and OCT3, 46 other reports have shown no differences in agmatine transport by hOCT1 and hOCT3, and an approximately 40% reduction in agmatine accumulation by hOCT2 over-expressing cells. 47 Since further clarification is warranted, we investigated the involvement of the human transporters OCT1, OCT2, and MATE1 in agmatine and putrescine transport. The expression and localization of these transporters may determine agmatine cellular disposition, and the correspondent role of agmatine in physiological phenomenon related to the modulation of intracellular polyamines.…”

Section: Discussionmentioning

confidence: 99%

OCT2 and MATE1 Provide Bidirectional Agmatine Transport

2010

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Agmatine is a biogenic amine (l-arginine metabolite) of potential relevance to several central nervous system (CNS) conditions. The identities of transporters underlying agmatine and polyamine disposition in mammalian systems are not well defined. The SLC-family organic cation transporters (OCT) OCT1 and OCT2 and multidrug and toxin extrusion transporter-1 (MATE1) are transport systems that may be of importance for the cellular disposition of agmatine and putrescine. We investigated the transport of [3H]-agmatine and [3H]-putrescine in human embryonic kidney (HEK293) cells stably-transfected with hOCT1-, hOCT2-, and hMATE1. Agmatine transport by hOCT1 and hOCT2 was concentration-dependent, whereas only hOCT2 demonstrated pH-dependent transport. hOCT2 exhibited a greater affinity for agmatine (Km = 1.84 ± 0.38 mM) than did hOCT1 (Km = 18.73 ± 4.86 mM). Putrescine accumulation was pH- and concentration-dependent in hOCT2-HEK cells (Km = 11.29 ± 4.26 mM) but not hOCT1-HEK cells. Agmatine accumulation, in contrast to putrescine, was significantly enhanced by hMATE1 over-expression, and was saturable (Km = 240 ± 31 μM; Vmax = 192 ± 10 pmol/min/mg protein). Intracellular agmatine was also trans-stimulated (effluxed) from hMATE1-HEK cells in the presence of an inward proton-gradient. The hMATE1-mediated transport of agmatine was inhibited by polyamines, the prototypical substrates MPP+ and paraquat, as well as guanidine and arcaine, but not l-arginine. These results suggest that agmatine disposition may be influenced by hOCT2 and hMATE1, two transporters critical in the renal elimination of xenobiotic compounds.

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“…Colon cells are exposed to particularly high concentrations of agmatine in the intestinal chyme. It has been suggested that intestinal availability of agmatine may have implications for the development of colon tumors and for tissue regeneration 24. Our objective was to clarify the interaction between intracellular agmatine concentration and cell proliferation in human gut‐derived cell lines and colon tumor resectates.…”

Section: Discussionmentioning

confidence: 99%

Intestinal tumor and agmatine (decarboxylated arginine)

Molderings

Kribben

Heinen

et al. 2004

Cancer

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BACKGROUND.The polyamine system is a promising target for anticancer therapy.Ideally, an antineoplastic compound affecting this system should inhibit both ornithine decarboxylase and the polyamine transporter, and toxicity should be mild. Agmatine, decarboxylated L-arginine, appears to be such a compound. METHODS.Adenosine triphosphate levels and the protein content of cell populations in culture were identified as surrogate markers for cell count. Agmatine content in cells and tissue specimens was measured by high-performance liquid

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Pharmacological characteristics of the specific transporter for the endogenous cell growth inhibitor agmatine in six tumor cell lines

Cited by 14 publications

References 33 publications

Identification and Pharmacological Characterization of a Specific Agmatine Transport System in Human Tumor Cell Lines

Identification and Pharmacological Characterization of a Specific Agmatine Transport System in Human Tumor Cell Lines

OCT2 and MATE1 Provide Bidirectional Agmatine Transport

Intestinal tumor and agmatine (decarboxylated arginine)

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