The physiological role of biogenic amines redox reactions in mitochondria. New perspectives in cancer therapy.
In tumours, polyamines and amine oxidases increase 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. Increasing the incubation temperature from 37 to 42 degrees C enhances cytotoxicity in cells exposed to spermine metabolites. The combination BSAO/spermine prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. Since the tumour cells release endogenous substrates of BSAO, the administration of spermine is not required. Combination with hyperthermia improves the cytocidal effect of polyamines oxidation products. Our findings show that multidrug resistant (MDR) cells are more sensitive to spermine metabolites than their wild-type counterparts, due to an increased mitochondrial activity which induces the generation of intracellular ROS prior to the onset of mitochondrial permeability transition (MPT). It makes this new approach attractive, since the development of MDR is one of the major problems of conventional cancer therapy.
Agostinelli
E
E
Department of Biochemical Sciences A. Rossi Fanelli, Institute of Molecular Biology and Pathology, University of Rome La Sapienza and CNR, Rome, Italy. enzo.agostinelli@uniroma1.it
Tempera
G
G
Molinari
A
A
Salvi
M
M
Battaglia
V
V
Toninello
A
A
Arancia
G
G
D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006979:Hyperthermia, Induced; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D008995:Monoamine Oxidase / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
D015317:Biogenic Polyamines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D008995:Monoamine Oxidase