Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach.
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.
Agostinelli
E
E
Department of Biochemical Sciences - SAPIENZA University of Rome and CNR, Biology and Molecular Pathology Institutes, Piazzale Aldo Moro 5, 00185, Rome, Italy. enzo.agostinelli@uniroma1.it
Tempera
G
G
Viceconte
N
N
Saccoccio
S
S
Battaglia
V
V
Grancara
S
S
Toninello
A
A
Stevanato
R
R
D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D011073:Polyamines / Q000378:metabolism*; D013096:Spermine / Q000378:metabolism / Q000627:therapeutic use*
D011073:Polyamines; D013096:Spermine; D006631:Amine Oxidase (Copper-Containing)