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Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach

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Abstract

The polyamines spermine, spermidine and putrescine are ubiquitous cell components. These molecules are substrates of a class of enzymes that includes monoamine oxidases, diamine oxidases, polyamine oxidases and copper-containing amine oxidases. Amine oxidases are important because they contribute to regulate levels of mono- and polyamines. In tumors, polyamines and amine oxidases are increased as compared to normal tissues. Cytotoxicity induced by bovine serum amine oxidase (BSAO) and spermine is attributed to H2O2 and aldehydes produced by the reaction. This study demonstrated that multidrug-resistant (MDR) cancer cells (colon adenocarcinoma and melanoma) are significantly more sensitive than the corresponding wild-type (WT) ones to H2O2 and aldehydes, the products of BSAO-catalyzed oxidation of spermine. Transmission electron microscopy (TEM) observations showed major ultrastructural alterations of the mitochondria. These were more pronounced in MDR than in WT cells. Increasing the incubation temperature from 37 to 42°C enhances cytotoxicity in cells exposed to spermine metabolites. The combination BSAO/spermine prevents tumor growth, particularly well if the enzyme has been conjugated to a biocompatible hydrogel polymers. Since both wild-type and MDR cancer cells after pre-treatment with MDL 72527, a lysosomotropic compound, are sensitized to subsequent exposure to BSAO/spermine, it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumor cells. It is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting.

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Abbreviations

ADR:

Adriamycin-resistant cells

ALDH:

Aldehyde dehydrogenase

AO:

Amine oxidase

APAO:

N1-Acetylpolyamine oxidase

BSAO:

Bovine serum amine oxidase

CHO:

Chinese hamster ovary

CuAO:

Copper amine oxidase

Cu/TPQ-AO:

Amine oxygen oxidoreductase copper-containing

DAO:

Diamine oxidase

DFMO:

Difluoromethylornithine

DX:

Doxorubicin-resistant cells

FAD:

Flavin adenine dinucleotide

hVAP-1:

Human vascular adhesion protein-1

LoVo:

Colon adenocarcinoma cell

LOX:

Lysyl oxidase

M14:

Melanoma cell

MAO:

Monoamine oxidase

MDL 72527:

N1,N4-bis(2,3-butadienyl)-1,4-butanediamine

MDR:

Multidrug-resistant

NSAIDS:

Non-steroidal anti-inflammatory drugs

PAO:

Polyamine oxidase

PEG:

Polyethylene glycol

P-gp:

P-glycoprotein

ROS:

Reactive oxygen species

SAO:

Serum amine oxidase

SH:

Thiol groups

SMO:

Spermine oxidase

SSAO:

Semicarbazide-sensitive amine oxidase

TEM:

Transmission electron microscopy

LTQ:

Lysine tyrosylquinone

TNFα:

Tumor-necrosis factor α

TPQ:

2,4,5-Trihydroxyphenylalaninequinone

VAP-1:

Vascular adhesion protein-1

WR 1065:

Aminothiol N-(2-mercaptoethyl)-1,3-propanediamine

WT:

Wild-type

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Acknowledgments

This work was partially supported by the Italian MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca) and by funds MIUR-PRIN (Cofin). Thanks 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 – SAPIENZA University of Rome and CNR, Biology and Molecular Pathology Institutes, Piazzale Aldo Moro 5, 00185, Rome, Italy

    E. Agostinelli, G. Tempera, N. Viceconte & S. Saccoccio

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

    V. Battaglia, S. Grancara & A. Toninello

  3. Department of Physical Chemistry, University of Venice “Ca’ Foscari”, Dorsoduro 2137, 30123, Venice, Italy

    R. Stevanato

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  1. E. Agostinelli
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  2. G. Tempera
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  3. N. Viceconte
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Correspondence to E. Agostinelli.

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Agostinelli, E., Tempera, G., Viceconte, N. et al. Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids 38, 353–368 (2010). https://doi.org/10.1007/s00726-009-0431-8

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  • DOI: https://doi.org/10.1007/s00726-009-0431-8

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