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Synthesis and biological activity of 6-selenocaffeine: potential modulator of chemotherapeutic drugs in breast cancer cells.

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.

SUBMITTER: Martins IL

PROVIDER: S-EPMC6270583 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Synthesis and biological activity of 6-selenocaffeine: potential modulator of chemotherapeutic drugs in breast cancer cells.

Martins Inês L IL Miranda Joana P JP Oliveira Nuno G NG Fernandes Ana S AS Gonçalves Sandrina S Antunes Alexandra M M AM

Molecules (Basel, Switzerland) 20130508 5

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 h ...[more]

PMID: 23698041

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Project description:INTRODUCTION: Amphiphilic copolymer nanoparticle-encapsulated multi-target chemotherapeutic drugs have attracted considerable attention due to their favorable drug efficiency and potential application prospect. Studies have shown that an amphiphilic copolymer, methoxypoly(ethylene glycol)-poly(lactide-co-glycolide) modified with e-polylysine, and encapsulated with hydrophilic doxorubicin, hydrophobic paclitaxel and survivin siRNA profoundly improved the therapeutic effect both in vitro and in vivo.</br>OBJECTIVES: To investigate how MCF-7 cells would response to the exposure of these nanoparticles over with time and assess the biological effects of these nanoparticles and their encapsulated drugs in a holistic manner.</br>METHODS: MCF-7 cells were treated with PBS, nanocarrier and three encapsulated drugs, respectively. Metabolic alterations associated with nano-drugs exposure were investigated by performing untargeted NMR metabolomics with combination of targeted fatty acids analysis by GC-MS on cell extracts. Altered metabolic pathways were further validated by qRT-PCR approach.</br>RESULTS: Copolymers showed great biocompatibility with cells as it induced transit metabolic disruptions without affecting cell survival rate. The rapid release of encapsulated doxorubicin resulted in inhibition of glycolysis and DNA synthesis, active proteolysis; these metabolic alternations were recovered after 10 h exposure. However, the combination use of multiple drugs consistently induced cell cycle arrest and apoptosis evidenced by reduction in glycolysis, active proteolysis, stimulated O-GlcNAcylation, reduced the PC:GPC ratio and fatty acids accumulation. Prolonged exposure to encapsulated-multiple-drugs also induced oxidative stress to cells.</br>CONCLUSION: These findings provide important insight into the biological effects of nanoparticles and their encapsulated drugs while demonstrate that metabolomics is a powerful approach to evaluate the biological effects of nano-drugs.

Project description:Resisting chemotherapy is a significant hurdle in treating breast cancer. Locally advanced breast cancer patients undergo four cycles of Adriamycin and Cyclophosphamide, followed by four cycles of Paclitaxel before surgery. Some patients resist this regimen, and their cancer recurred. Our study aimed to understand the underlying mechanisms of acquired resistance during these specific treatment phases. We explored how breast cancer cells, resistant to chemotherapy, respond to different glucose levels, shedding light on the intricate relationship between diabetes, breast cancer subtype, and resistance to preoperative chemotherapy. We examined two groups of cell lines: the standard MDA-MB-231 and MCF7 cells and their resistant counterparts after exposure to four cycles of Adriamycin and cyclophosphamide (4xAC) or four cycles of 4xAC and Paclitaxel (4xAC+4xPAC), aiming to unravel the mechanisms and cellular responses at these critical treatment stages. Notably, under normal and low glucose conditions, the resistant MDA-MB-231 cells showed accelerated growth compared to the control cells, while the resistant MCF7 cells proliferated more slowly than their original counterparts. Resistance to 4xAC resulted in significant cell death in both cell lines, especially under low glucose conditions, in contrast to control or 4xAC+4xPAC-resistant cells. The similarity between the MCF7 4xAC+4xPAC resistant cells and the control might be due to the P-AKT expression pattern in response to glucose levels since the levels were constant in MCF7 4xAC in all glucose concentrations. Molecular analysis revealed specific protein accumulations explaining the heightened proliferation and invasion in resistant MDA-MB-231 cells and their ability to withstand low glucose levels compared to MCF7. In conclusion, increased drug involvement corresponds to increased cell resistance, and changes in glucose levels differentially impact resistant variant cells to different drugs. The findings can be translated clinically to explain patients' differential responses to preoperative chemotherapy cycles considering their breast cancer subtype and diabetic status.

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Synthesis and biological activity of 6-selenocaffeine: potential modulator of chemotherapeutic drugs in breast cancer cells.

Publications

Synthesis and biological activity of 6-selenocaffeine: potential modulator of chemotherapeutic drugs in breast cancer cells.

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