Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

This study examined agmatine transport into six human intestinal tumor cell lines and compared the pharmacological properties of this transporter with those of the agmatine carrier previously characterized in human glioblastoma cells.

Methods

Carrier-mediated uptake was determined as specific accumulation of [14C]agmatine in the cells. The changes in intracellular agmatine concentration in the tumor cells after 24 h incubation with 1 mM agmatine was analyzed by high-performance liquid chromatography.

Results

Specific [14C]agmatine accumulation was found in the six human intestinal tumor cell lines Caco2, Cx1, Colo320, HT29, Colo205E, and SW480. Specific [14C]agmatine accumulation was inhibited by phentolamine, putrescine, spermine, clonidine, and decynium-22 but not by corticosterone, O-methylisoprenaline, or l-carnitine. Incubation with exogenous agmatine for 24 h increased intracellular agmatine content in all cell lines by a multiple of the basal endogenous content. Transfection of HEK293 cells with cDNA encoding either hOCT1, hOCT2, or hOCT3 did not enhance [14C]agmatine accumulation compared to nontransfected cells.

Conclusion

All intestinal tumor cell lines investigated express a functional specific agmatine transporter which exhibit pharmacological characteristics similar to those of the agmatine transporter in glioblastoma cells. This agmatine carrier is not identical with any so far known organic cation transport system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Molderings GJ (1997) Imidazoline receptors: basic knowledge, recent advances and future prospects for therapy and diagnosis. Drugs Future 22:757–772

    CAS  Google Scholar 

  2. Raasch W, Schäfer U, Chun J, Dominiak P (2001) Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol 133:755–780

    CAS  PubMed  Google Scholar 

  3. Reis DJ, Regunathan S (1999) Agmatine: an endogenous ligand at imidazoline receptors is a novel neurotransmitter. Ann N Y Acad Sci 881:65–80

    CAS  PubMed  Google Scholar 

  4. Molderings GJ, Menzel S, Kathmann M, Schlicker E, Göthert M (2000) Dual interaction of agmatine with the rat α2D-adrenoceptor: competitive antagonism and allosteric activation. Br J Pharmacol 130:1706–1712

    CAS  PubMed  Google Scholar 

  5. Marton LJ, Pegg AE (1995) Polyamines as targets for therapeutic intervention. Annu Rev Pharmacol Toxicol 35:55–91

    CAS  PubMed  Google Scholar 

  6. Jänne J, Pös H, Raina A (1978) Polyamines in rapid growth and cancer. Biochim Biophys Acta 473:241–293

    PubMed  Google Scholar 

  7. Berdinskikh NK, Ignatenko NA, Zaletok SP, Ganina KP, Chorniy VA (1991) Ornithine decarboxylase activity and polyamine content in adenocarcinomas of human stomach and large intestine. Int J Cancer 47:496–498

    CAS  PubMed  Google Scholar 

  8. Leveque J, Foucher F, Bansard JY, Havouis R, Grall JY, Moulinoux JP (2000) Polyamine profiles in tumor, normal tissue of the homologous breast, blood, and urine of breast cancer sufferers. Breast Cancer Res Treat 60:99–105

    Article  CAS  PubMed  Google Scholar 

  9. Rozhin J, Wilson P, Bull A, Nigro N (1984) Ornithine decarboxylase activity in rat and human colon. Cancer Res 44:3226–3230

    CAS  PubMed  Google Scholar 

  10. Herrera-Ornelas L, Porter C, Pera P, Greco W, Petrelli N, Mittelman A (1987) A comparison of ornithine decarboxylase and S-adenosylmethionine decarboxylase activity in human large bowel mucosa, polyps and colorectal adenocarcinoma. J Surg Res 42:56–60

    CAS  PubMed  Google Scholar 

  11. Porter C, Herrera-Ornelas L, Pera P, Petrelli N, Mittelman A (1987) Polyamine biosynthetic activity in normal and neoplastic human colorectal tissue. Cancer 60:1275–1281

    CAS  PubMed  Google Scholar 

  12. Gökmen SS, Aygit AC, Ayhan MS, Yorulmaz F, Gülen S (2001) Significance of arginase and ornithine in malignant tumors of the human skin. J Lab Clin Med 137:340–344

    Article  PubMed  Google Scholar 

  13. d'Agostino L, Pignata S, Daniele B, d'Adamo G, Ferraro C, Silvestro G, Tagliaferri P, Contegiacomo A, Gentile R, Tritto G (1990) Polyamine uptake by human colon carcinoma cell line CaCo2. Digestion 46 [Suppl 2]:352–359

  14. Til HP, Falke HE, Prinsen MK, Willems MI (1997) Acute and subacute toxicity of tyramine, spermidine, spermine, putrescine and cadaverine in rats. Food Chem Toxicol 35:337–348

    Article  CAS  PubMed  Google Scholar 

  15. Schipper RG, Deli G, Deloyer P, Lange WP, Schalken JA, Verhifstad AA (2000) Antitumor activity of polyamine analog N (1),N (11)-diethylnorspermine against human prostate carcinoma cells. Prostate 44:313–321

    Article  CAS  PubMed  Google Scholar 

  16. Raasch W, Schäfer U, Qadri F, Dominiak P (2002) Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction. Br J Pharmacol 135:663–672

    CAS  PubMed  Google Scholar 

  17. Satriano J, Blantz RC, Kelly CJ (1998) Methods of using agmatine to reduce intracellular polyamine levels and to inhibit inducible nitric. Patent WO9813037A1

  18. Choi YS, Cho YD (1999) Effects of agmatine on polyamine metabolism and the growth of prostate tumor cells. J Biochem Mol Biol 32:173–180

    CAS  Google Scholar 

  19. Mates JM, Sanchez-Jimenez F, Lopez-Herrera J, de Castro IN (1991) Regulation by 1:4-diamines of the ornithine decarboxylase activity induced by ornithine in perifused tumor cells. Biochem Pharmacol 42:1045–1052

    Article  CAS  PubMed  Google Scholar 

  20. Satriano J, Matsufuji S, Murakami, Y, Lortie MJ, Schwartz D, Kelly CJ, Hayashi S, Blantz RC (1998) Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. J Biol Chem 273:15313–15316

    CAS  PubMed  Google Scholar 

  21. Satriano J, Isome M, Casero RA, Thomson SC, Blantz RC (2001) Polyamine transport system mediates agmatine transport in mammalian cells. Am J Cell Physiol 281:C329–C334

    CAS  Google Scholar 

  22. Molderings GJ, Bönisch H, Göthert M, Brüss M (2001) Agmatine and putrescine uptake in the human glioma cell line SK-MG-1. Naunyn-Schmiedebergs Arch Pharmacol 363:671–679

    Article  CAS  Google Scholar 

  23. Satriano J, Kelly CJ, Blantz RC (1999) An emerging role for agmatine. Kidney Int 56:1252–1253

    Article  CAS  PubMed  Google Scholar 

  24. Vargiu C, Cabella C, Belliardo S, Cravanzola C, Grillo MA, Colombatto S (1999) Agmatine modulates polyamine content in hepatocytes by inducing spermidine/spermine acetyltransferase. Eur J Biochem 259:933–938

    PubMed  Google Scholar 

  25. Molderings GJ, Heinen A, Menzel S, Göthert M (2002) Exposure of rat isolated stomach and rats in vivo to [14C]agmatine: accumulation in the stomach wall and distribution in various tissues. Fundam Clin Pharmacol 16:219–225

    Google Scholar 

  26. Hayer-Zillgen M, Brüss M, Bönisch H (2002) Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol 136:829–836

    Article  CAS  PubMed  Google Scholar 

  27. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  28. Raasch W, Regunathan S, Li G, Reis DJ (1995) Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci 56:2319–2330

    CAS  PubMed  Google Scholar 

  29. Molderings GJ, Burian M, Homann J, Nilius M, Göthert M (1999) Potential relevance of agmatine as a virulence factor of Helicobacter pylori. Dig Dis Sci 44:2397–2404

    CAS  PubMed  Google Scholar 

  30. Martel F, Gründemann D, Calhau C, Schömig E (2001) Apical uptake of organic cations by human intestinal Caco2-cells: putative involvement of ASF transporters. Naunyn-Schmiedebergs Arch Pharmacol 363:40–49

    Article  CAS  Google Scholar 

  31. Osborne DL, Moshier JA, Gesell MS, Luk GD (1992) Polyamine uptake in tumorigenic and non-tumorigenic cell lines and the influence of extracellular putrescine on human colon cancer cells. In: Dowling RH, Fölsch UR (eds) Polyamines in the gastrointestinal tract. Kluwer, Dordrecht, pp 323–334

  32. Cabella C, Gardini G, Corpillo D, Testore G, Bedino G, Solinas SP, Cravanzola C, Vargiu C, Grillo MA, Colombatto S (2001) Transport and metabolism of agmatine in rat hepatocyte cultures. Eur J Biochem 268:940–947

    Article  CAS  PubMed  Google Scholar 

  33. Babal P, Obson JW, Gillespie MN (1999) Agmatine suppresses polyamine transport in pulmonary artery smooth muscle cells. FASEB J 13:A827

    Google Scholar 

  34. Valle AE del, Paz JC, Sanchez-Jimenez F, Medina MA (2000) Agmatine uptake by cultured hamster kidney cells. Biochem Biophys Res Commun 280:307–311

    Article  Google Scholar 

  35. Barendt WM, Wright SH (2002) The human organic cation transporter (hOCT2) recognizes the degree of substrate ionization. J Biol Chem 277:22491–22496

    Google Scholar 

  36. Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Shimanes M, Sai Y, Tsuji A (1998) Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem 273:20378–20382

    CAS  PubMed  Google Scholar 

  37. Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leibach FH, Chen J, Conway SJ, Ganapathy V (1999) Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther 290:1482–1492

    Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft and the Wilhelm-Sander-Stiftung. The technical assistance of Mrs. D. Funccius, Mrs. M. Hartwig, and Mrs. R. Müller is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Bonn, Reuterstrasse 2b, 53113, Bonn, Germany

    A. Heinen, M. Brüss, H. Bönisch, M. Göthert & G. J. Molderings

Authors
  1. A. Heinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Brüss
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Bönisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Göthert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. J. Molderings
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. J. Molderings.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heinen, A., Brüss, M., Bönisch, H. et al. Pharmacological characteristics of the specific transporter for the endogenous cell growth inhibitor agmatine in six tumor cell lines. Int J Colorectal Dis 18, 314–319 (2003). https://doi.org/10.1007/s00384-002-0466-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-002-0466-8

Keywords

Search

Navigation