Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: sensitization by the MDL 72527 lysosomotropic compound.
It has been confirmed that multidrug resistant (MDR) human melanoma cells are more sensitive than their wild-type counterparts 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 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. 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.
Agostinelli
Enzo
E
Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, Italy. enzo.agostinelli@uniroma1.it
Condello
Maria
M
Molinari
Agnese
A
Tempera
Giampiero
G
Viceconte
Nikenza
N
Arancia
Giuseppe
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010084:Oxidation-Reduction; D011700:Putrescine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013096:Spermine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C044445:MDL 72527; D013096:Spermine; D011700:Putrescine