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Polyamines: fundamental characters in chemistry and biology

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Abstract

Polyamines are small cationic molecules required for cellular proliferation and are detected at higher concentrations in most tumour tissues, compared to normal tissues. Agmatine (AGM), a biogenic amine, is able to arrest proliferation in cell lines by depleting intracellular polyamine levels. It enters mammalian cells via the polyamine transport system. Agmatine is able to induce oxidative stress in mitochondria at low concentrations (10 or 100 μM), while at higher concentrations (e.g. 1–2 mM) it does not affect mitochondrial respiration and is ineffective in inducing any oxidative stress. As this effect is strictly correlated with the mitochondrial permeability transition induction and the triggering of the pro-apoptotic pathway, AGM may be considered as a regulator of this type of cell death. Furthermore, polyamine transport is positively correlated with the rate of cellular proliferation. By increasing the expression of antizyme, a protein that inhibits polyamine biosynthesis and transport, AGM also exhibits a regulatory effect on cell proliferation. Methylglyoxal bis(guanylhydrazone) (MGBG), a competitive inhibitor of S-adenosyl-l-methionine decarboxylase, displaying anticancer activity, is a structural analogue of the natural polyamine spermidine. MGBG has been extensively studied, preclinically as well as clinically, and its anticancer activity has been attributed to the inhibition of polyamine biosynthesis and also to its effect on mitochondrial function. Numerous findings have suggested that MGBG might be used as a chemotherapeutic agent against cancer.

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Abbreviations

ADC:

Arginine decarboxylase

AGM:

Agmatine (4-(aminobutyl)guanidine)

AO-Agm:

N-(3-aminoxy-propyl)-guanidin

BSAO:

Bovine serum amine oxidase

DFMO:

(d, l)-2-(difluoromethyl)ornithine

EMT:

Extraneuronal monoamine transporter

GAPA:

N-(3-aminopropoxy)guanidine

INS:

Inelastic neutron scattering

IR:

Infrared spectroscopy

MDR:

Multidrug resistant

MGBG:

Methylglyoxal bis(guanylhydrazone)

MPT:

Mitochondrial permeability transition

NGPG:

N-(3-guanidino-propoxy)guanidine

OCT2:

Organic cation transporter 2

ODC:

Ornithine decarboxylase

PAs:

Polyamines

RLM:

Rat liver mitochondria

ROS:

Reactive oxygen species

SAMDC:

S-adenosyl-l-methionine decarboxylase

SAR’s:

Structure–activity relationships

SSAT:

Spermidine/spermine N-acetyltransferase

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Acknowledgments

MPMM acknowledges financial support from the Portuguese Foundation for Science and Technology (FCT)—Project PTDC/QUI/66701/2006 (co-financed by the European Community fund FEDER). Thanks are due to the Italian MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca) and MIUR-PRIN-Cofin (EA). Thanks are due to ‘Fondazione Sovena’ for the scholarship given to Nikenza Viceconte for supporting her Ph.D.

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Authors and Affiliations

  1. Department of Biochemical Sciences, Biology and Molecular Pathology Institutes, SAPIENZA University of Rome and CNR, Piazzale Aldo Moro 5, 00185, Rome, Italy

    E. Agostinelli, G. Tempera & N. Viceconte

  2. Department of Biochemical Sciences, SAPIENZA University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy

    E. Agostinelli

  3. Molecular Physical-Chemistry, R&D Unit University of Coimbra, Coimbra, Portugal

    M. P. M. Marques & R. Calheiros

  4. CEMDRX, Physics Department, University of Coimbra, Coimbra, Portugal

    F. P. S. C. Gil

  5. Department of Biological Chemistry, University of Padua, 35121, Padua, Italy

    V. Battaglia, S. Grancara & A. Toninello

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  1. E. Agostinelli
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Agostinelli, E., Marques, M.P.M., Calheiros, R. et al. Polyamines: fundamental characters in chemistry and biology. Amino Acids 38, 393–403 (2010). https://doi.org/10.1007/s00726-009-0396-7

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