title: The combined treatment with chloroquine and the enzymatic oxidation products of spermine overcomes multidrug resistance of melanoma M14 ADR2 cells: a new therapeutic approach.
abstract: It has been confirmed that multidrug resistant (MDR) melanoma cells (M14 ADR2) are more sensitive than their wild-type counterparts (M14 WT) to H2O2 and aldehydes, the products of bovine serum amine oxidase (BSAO)-catalyzed oxidation of spermine. The metabolites formed by BSAO and spermine are more toxic, in M14 cells, than exogenous H2O2 and acrolein, even though their concentration is lower during the initial phase of incubation due to their more gradual release than the exogenous products. Binding of BSAO to the cell membrane and release of the reaction products of spermine into the immediate vicinity of the cells, or directly into the cells, may explain the apparently paradoxical phenomenon. Both WT and MDR cells, after pre-treatment for 24 h, or longer, with the lysosomotropic compound chloroquine (CQ), show to be sensitized to subsequent exposure to BSAO/spermine enzymatic system. Evidence of ultrastructural aberrations and acridine orange release from lysosomes is presented in this study that is in favor of the permeabilization of the lysosomal membrane as the major cause of sensitization by CQ. Pre-treatment with CQ amplifies the ability of the metabolites formed from spermine by oxidative deamination to induce cell death. Melanocytes, differently from melanoma cells, were unaffected by the enzymatic system, even when preceded by CQ treatment. Since it is conceivable that combined treatment with a lysosomotropic compound and BSAO/spermine would be effective against tumour cells, it is of interest to search for such novel compounds, which might be promising for application in a therapeutic setting.
authors: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Biochemical Sciences, Sapienza University of Rome and CNR, Ι-00185 Rome, Italy.
authors: Enzo
authors: E
authors: Agostinelli
authors: Department of Technology and Health, Italian National Institute of Health, I-00161 Rome, Italy.
authors: Maria
authors: M
authors: Condello
authors: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Biochemical Sciences, Sapienza University of Rome and CNR, Ι-00185 Rome, Italy.
authors: Giampiero
authors: G
authors: Tempera
authors: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Biochemical Sciences, Sapienza University of Rome and CNR, Ι-00185 Rome, Italy.
authors: Alberto
authors: A
authors: Macone
authors: Department of Technology and Health, Italian National Institute of Health, I-00161 Rome, Italy.
authors: Giuseppina
authors: G
authors: Bozzuto
authors: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Biochemical Sciences, Sapienza University of Rome and CNR, Ι-00185 Rome, Italy.
authors: Shinji
authors: S
authors: Ohkubo
authors: Department of Technology and Health, Italian National Institute of Health, I-00161 Rome, Italy.
authors: Annarica
authors: A
authors: Calcabrini
authors: Department of Technology and Health, Italian National Institute of Health, I-00161 Rome, Italy.
authors: Giuseppe
authors: G
authors: Arancia
authors: Department of Technology and Health, Italian National Institute of Health, I-00161 Rome, Italy.
authors: Agnese
authors: A
authors: Molinari
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008544:Melanocytes / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy*; D010084:Oxidation-Reduction; D013096:Spermine / Q000494:pharmacology*
chemical_list: D013096:Spermine; D002738:Chloroquine