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Area 4: Molecular recognition in biomolecules Toxic effects induced by polyamine metabolites on melanoma cells:
a new therapeutic approach
Enzo Agostinelli
Department of Biochemical Sciences "A. Rossi Fanelli" ℡: +39 06 49910838 - @: The purpose of this research is to develop a new anticancer therapy against melanoma (M14), taking advantage of the high polyamine content of tumor cells, since such polycations may become a source of cytotoxic metabolites. For their generation an enzyme, bovine serum amine oxidase (BSAO) will be employed. It is expected that by delivering BSAO into cancer cells, toxic enzymatic oxidation products could be produced intracellularly for selective killing in situ. Several studies have been performed to overcome the drug-resistant phenotype and to develop innovative chemotherapeutic strategies effective against multi-drug resistant (MDR) tumours. Our studies demonstrate that BSAO and spermine (SPM) addition to human M14 cells induces cell growth inhibition and overcomes the MDR phenotype (ADR2). The oxidative reaction produces polyamine metabolites (H2O2 and aldehydes) which induce oxidative stress. Cytotoxicity induced by SPM metabolites was greater in MDR cells than in wild-type ones (WT), due to an increased mitochondrial activity. To increase the induction of cell death by toxic polyamine metabolites, we are currently investigating several drug combinations. Clonogenic experiments showed that the cytotoxicity induced by BSAO/SPM addition was enhanced by the pre-treatment of tumour cells with lysosomotropic compounds, the drug chloroquine (CQ) or MDL 72527, in both WT and MDR M14 cells. The pre-treatment of M14 cells with CQ or MDL 72527 sensitized both WT and ADR2 cells to the subsequent exposure to SPM metabolites. Noteworthy, the apoptotic effect was higher in ADR2 cells than in their WT counterparts. The cytotoxic effect induced by the combined treatment was characterized by cytoplasmic vacuolization and mitochondrial damage, as revealed by transmission electron microscopy (TEM) (Fig. 1). We hypothesize that the release of lysosomal enzymes produces oxidative stress and apoptosis, indicating a contribution of the lysosomotropic properties of CQ to the sensitization of M14 cells to H2O2 and aldehyde(s). The findings suggest that the association of BSAO/SPM with CQ or MDL 72527, and mitochondrial alterations induced by SPM oxidation products, allow the design of a new therapeutic strategy based on the use of these combinations in human neoplasms, making this approach mainly attractive in treating MDR cancer patients. From a therapeutic point of view the improvement of the efficacy of in situ formation of cytotoxic polyamines metabolites is essential. Since in the present model H2O2 and aldehydes are produced outside the cells, the main challenge will be to deliver BSAO into cancer cells in order to induce their selective killing by the cytotoxic factors produced intracellularly from endogenous polyamines. Therefore, strategies could be developed to find Area 4: Molecular recognition in biomolecules how the enzyme could be delivered in vivo. To this aim BSAO incorporates into liposomal
vesicles and dedicated nano-scale drug delivery systems will be designed. Thus,
endogenous polyamines present in high concentration in tumor cells could be targeted and
oxidized by the enzyme.

Fig. 1
- Ultrastructural analysis of M14 WT ( top
panels) and M14 ADR2 (lower panels) cells
performed by TEM. (a and b) Untreated melanoma
cells; (c and d) Cells exposed to 300 µM MDL 72527
for 24 h, at 37˚C; (e and f) Cells treated for 60 min
with 6.5x10-3 IU/ml BSAO and6 µM SPM at 37˚C; (g
and h) Cells were first exposed for 24 h to 300 µM
MDL 72527, and then treated for 60 min with
6.5x10-3 IU/ml BSAO and 6 µM SPM at 37˚C.

Agostinelli E. Role of polyamines, their analogs and transglutaminases in biological and
clinical perspectives. Amino Acids 2011 Epub. doi: 10.1007/s00726-011-1129-2 Agostinelli E, Toninello A, Vianello F, Stevanato R. Do mammalian amine oxidases and the mitochondrial polyamine transporter have similar protein structures? Amino Acids 2011 Epub. doi: 10.1007/s00726-011-0988-x. Stevanato R, Cardillo S, Braga M, De Iuliis A, Battaglia V, Toninello A, Agostinelli E, Vianello F. Preliminary kinetic characterization of a copper amine oxidase from rat liver mitochondria matrix. Amino Acids 2011, 40: 713–20. doi: 10.1007/s00726-010-0708-y. Valente S, Tomassi S, Tempera G, Saccoccio S, Agostinelli E, Mai A. Novel Reversible Monoamine Oxidase A Inhibitors: Highly Potent and Selective 3-(1H-Pyrrol-3-yl)-2- oxazolidinones. J Med Chem 2011, 54: 8228-32. Epub 2011 Nov 7. doi: 10.1021/ jm201011x.
Research Group
Paola Turini, professor; Giampiero Tempera,
Annarica Calcabrini, Istituto Superiore di
Nikenza Viceconte, Stefania Saccoccio, post-
Sanità, Roma; Taichi Ueshima, Wakunaga


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