Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound

Abstract

Abstract. It has been confirmed that multidrug resistant (MDR) human melanoma cells are more sensitive than their wild-type counterparts to H 2 O 2 and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. The metabolites formed by BSAO and spermine are more toxic than exogenous H 2 O 2 and acrolein, even though their concentration is lower during the initial phase of incubation due to their more gradual release than the exogenous products. Both wild-type and MDR cells, after pre-treatment with MDL 72527, an inactivator of polyamine oxidase and a lysosomotropic compound, show to be sensitized to subsequent exposure to BSAO/spermine. Evidence of ultrastructural aberrations and acridine orange release from lysosomes is presented in this work that is in favor of the permeabilization of the lysosomal membrane as the major cause of sensitization by MDL 72527. Owing to its lysosomotropic effect, pre-treatment with MDL 72527 amplifies the ability of the metabolites formed from spermine by oxidative deamination to induce cell death. Since 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.

Polyamines and α-Carbonic Anhydrases

“…Such a concept was proved by means of the experiment reported in Scheme 1 [13]. Oxidative deamination of spermine 3 catalyzed by the bovine serum amine oxidase (BSAO) [13].…”

“…Such a concept was proved by means of the experiment reported in Scheme 1 [13]. Putrescine 1, spermidine 2 and spermine 3 represent the main pool of polyamines in the eukaryotic cells and are all derived from decarboxylation reactions of ornithine or S-adenosyl-methionine amino acids by the enzyme ornithine decarboxylase (ODC) [8].…”

“…Then the dialdehyde intermediate 4 underwent a β-elimination to the shorter polyamine putrescine 1 and acrolein 4. The overall result of the high-molecular-weight polyamines' catabolism, such as that of spermine 3, is the formation of highly cytotoxic metabolites, which in turn are responsible for triggering cell death via apoptotic or non-apoptotic pathways [13]. It is clear that the polyamines' transformation into biological systems is also linked to the regulation of cell proliferation and death events.…”

Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives

“…Mono-, di-and poly-amines, as well as several N-acyl amines, are oxidatively deaminated by AOs in a reaction consuming O 2 and H 2 O. In fact, experiments were performed to induce cytotoxicity in several human tumor cell lines in vitro using purified bovine serum amino oxidase (BSAO), a CuAOs, in the presence of exogenous spermine or endogenous polyamines (Calcabrini et al 2002;Agostinelli et al 2009) or after injection of the enzyme into the tumor in vivo (Averill-Bates et al 2005). Amine oxidases preferentially use polyamines (spermine and spermidine) as substrate to generate the reactive oxygen species (ROS), H 2 O 2 , and aldehyde(s) (Agostinelli and Seiler 2006a).…”

Role of polyamines, their analogs and transglutaminases in biological and clinical perspectives

“…Mono-, di-and polyamines, as well as several N-acyl amines, are oxidatively deaminated by AOs in the presence of O 2 and H 2 O. The possibility of using purified bovine serum amino oxidase (BSAO) in the presence of exogenous spermine or endogenous polyamines to induce cytotoxicity in several human tumor cell lines in vitro (Calcabrini et al 2002;Agostinelli et al 2009) or injecting the enzyme into the tumor in vivo (Averill-Bates et al 2005) has been described. Amine oxidases metabolize preferentially polyamines (spermine and spermidine) to generate the reaction products H 2 O 2 and aldehyde(s) .…”