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

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 H(2)O(2) 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 H(2)O(2) 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 degrees Celsius 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.

Polyamines and transglutaminases: future perspectives

“…The mechanistic aspects of these oxidase activities, excluding SMO, are known, and their cofactors and preferred polyamines as substrates have been characterized. Amine oxidases can be classified as Cu 2+ containing (or semicarbazide-sensitive), such as diamine oxidases, vascular-adhesion protein-1 and lysiloxidases, and FADdependent AOs (including monoamine, polyamine, and spermine oxidases; see Table 1 in Agostinelli et al (2010).…”

“…Amine oxidases (AOs) regulate the levels of polyamines and generate cytotoxic metabolites Agostinelli et al 2004). Interestingly, spermine oxidase (SMO), a FAD-containing enzyme, specifically oxidizes spermine (Spm) and SMO dysregulation alters polyamine homeostasis, participating in the aetiology of several pathological conditions, including cancer (Amendola et al 2009;Agostinelli et al 2010;Casero and Pegg 2010). Direct mechanistic links between inflammation, SMO activity, ROS production and carcinogenesis have been demonstrated (Goodwin et al 2008).…”

Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives

“…These toxic products are able to induce stress-activated signal transduction pathways, leading to cell death by necrosis or apoptosis (Lindsay and Wallace 1999;Seiler and Raul 2005;Agostinelli et al 2006b). These findings have a potential clinical application in cancer therapy Agostinelli et al 2004Agostinelli et al , 2010Averill-Bates et al 2008;Vijayanathan et al 2013;Amendola et al 2013). In light of this, a novel kind of super paramagnetic maghemite nanoparticles (SAMNs, surface active maghemite nanoparticles) were modified with BSAO, using rhodamine-isothiocyanate adduct as fluorescent spacer arm.…”

Anti‐Metastatic and Anti‐Angiogenic Activities of Core–Shell SiO2@LDH Loaded with Etoposide in Non‐Small Cell Lung Cancer

“…Nanoparticles have captured much attention, for example, their use as gene transporters, drug carriers, radioactive tracers, and therapies in medicine and other relevant fields 6, 7, 8. Amongst the known existing approaches, nanoparticles have prominent advantages in biosafety, targeting, and releasing control 9, 10…”