ABSTRACT
We report the development of a new microwave-based synthetic methodology mediated by Woollins' reagent that allowed an efficient conversion of caffeine into 6-selenocaffeine. A preliminary evaluation on the modulation of antioxidant activity upon selenation of caffeine, using the DPPH assay, indicated a mild antioxidant activity for 6-selenocaffeine, contrasting with caffeine, that exhibited no antioxidant activity under the same experimental conditions. Interestingly, whereas 6-selenocaffeine has revealed to have a low cytotoxic potential in both MCF10A and MCF-7 breast cells (24 h, up to 100 µM, MTT assay), a differential effect was observed when used in combination with the anticancer agents doxorubicin and oxaliplatin in MCF-7 breast cancer cells. The co-treatment of doxorubicin (1 µM) and 6-selenocaffeine (100 µM) resulted in a slight decrease in cellular viability when compared to doxorubicin (1 µM) alone. Conversely, the seleno-caffeine derivative at the same concentration markedly increased the viability of oxaliplatin (100 µM)-treated cells (p < 0.01). Overall, this work highlights an emerging methodology to synthesize organoselenium compounds and points out the differential roles of 6-selenocaffeine in the modulation of the cytotoxicity of anticancer agents.
Subject(s)
Antioxidants , Breast Neoplasms/drug therapy , Caffeine , Epithelial Cells/metabolism , Mammary Glands, Human/metabolism , Organoselenium Compounds , Antibiotics, Antineoplastic/agonists , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Caffeine/agonists , Caffeine/analogs & derivatives , Caffeine/chemical synthesis , Caffeine/chemistry , Caffeine/pharmacology , Cell Line, Tumor , Doxorubicin/agonists , Doxorubicin/pharmacology , Drug Agonism , Epithelial Cells/pathology , Female , Humans , Mammary Glands, Human/pathology , Organoplatinum Compounds/agonists , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Organoselenium Compounds/agonists , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , OxaliplatinABSTRACT
Diphenyl diselenide (PhSe)(2) is a synthetic organoselenium compound displaying glutathione peroxidase-like activity. Protective and antioxidant potential of (PhSe)(2) have been extensively investigated in in vivo and in vitro studies. In spite of this, there is a lack of studies addressed to the investigation of potential cytotoxic effect and signaling pathways modulated by this compound. Herein, we aimed to analyze the effects of 24-h treatment with (PhSe)(2) on cell viability and a possible modulation of signaling pathways in human neuroblastoma cell line SH-SY5Y. For this purpose, cells were incubated with (PhSe)(2) (0.3-30 µM) for 24 h and cell viability, apoptotic cell death and modulation of MAPKs (ERK1/2 and p38(MAPK)), and PKC substrates phosphorylation was determined. (PhSe)(2) treatment significantly decreased cell viability and increased the number of apoptotic cells with induction of PARP cleavage. An increase in ERK1/2 phosphorylation was observed at (PhSe)(2) 3 µM. In contrast, higher concentrations of the chalcogenide inhibited ERK1/2, p38(MAPK) and PKC substrate phosphorylation. Pre-treatment with ERK1/2 inhibitor, U0126, increased cell susceptibility to (PhSe)(2). Together, these data indicate a cytotoxic potential of (PhSe)(2) in a neuronal cell line, which appears to be mediated by the ERK1/2 pathway.
