A NEW THERAPEUTIC APPROACH USING THE COMBINED TREATMENT OF CHLOROQUINE WITH ENZYMATIC SPERMINE METABOLITES
Molinari Agnese (a), Condello Maria (a), Bozzuto Giuseppina (a), Calcabrini Annarica (a), Meringolo Martina (b), Ohkubo Shinji (b), Tempera Giampiero (b), Arancia Giuseppe (a), Agostinelli Enzo (b) (a) Department of Technology and Health, Italian National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy (b) Department of Biochemical Sciences, “Sapienza” University of Rome and CNR, Biology and Molecular Pathology Institutes, Piazzale A. Moro 5, 00185 Rome, Italy Presenting author: Molinari Agnese e-mail:
In the development of new treatments against tumours the differences between normal
and cancer cells must be considered. One of such differences is concerned with the polyamine content and metabolism. The content of polyamines, such as putrescine, spermidine and spermine (Spm), is increased in tumour cells in comparison with their normal counterparts. Increased polyamine levels are associated with increased cell proliferation, decreased apoptosis and down-expression of genes affecting tumour invasion and metastasis. Moreover, the natural polyamines are also source of cytotoxic metabolites, because they are substrates of a large class of enzymes, named amine oxidases. Our previous studies demonstrated that these enzymes catalyze the oxidative deamination of polyamines to generate cytotoxic products, H2O2 and aldehydes, that induce apoptotic and non apoptotic cell death. Such products also proved to induce a higher cell death on MDR melanoma cells than on the corresponding wild-type cells. It was demonstrated that the combination of BSAO/Spm with either docetaxel or interferon alpha had a synergistic effect on the inhibition of cell growth through apoptosis in both human epidermoid KB and breast cancer MCF-7 cell lines. Noticeably, our previous studies demonstrated that the induction of cell death, in colon adenocarcinoma (LoVo) and melanoma (M14) cancer cells, was potentiated by the combined treatments of BSAO/Spm with MDL72527 [N1,N4-bis(2,3-butadienyl)-1,4-butanediamine dihydrochloride], an inactivator of flavin-adenin-dinucleotide (FAD)-dependent amine oxidase (AO) with lysosomotropic properties. Thus, the aim of this study was to verify if also chloroquine (CQ), 4-aminoquinoline, a well known lysosomotropic compound, was able to sensitize tumour cells to the cytotoxic activity of spermine metabolites. CQ is a drug widely used for the therapy of malaria, and as an anti-inflammatory agent for the treatment of several diseases, like rheumatoid arthritis, lupus erythematosus and amoebic hepatitis, by targeting the polyamine pathway. Thus, a systematic exploration of this group of compounds in cancer therapy seems of interest. Recently, CQ has been studied as an enhancing agent in cancer therapy. In the present study the effect of pre-treatment with CQ, on the cytotoxicity of the spermine metabolites, was evaluated on wild-type human melanoma cells (M14 WT) and the corresponding doxorubicin-induced MDR cells (M14 ADR2).
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