Abstract
The effect of the treatment with glycolipid derivatives on the metabolic profile of intact glioma cells and tumor tissues, investigated using proton high resolution magic angle spinning (1H HR-MAS) nuclear magnetic resonance (NMR) spectroscopy, is reported here. Two compounds were used, a glycoside and its thioglycoside analogue, both showing anti-proliferative activity on glioma C6 cell cultures; however, only the thioglycoside exhibited antitumor activity in vivo. At the drug concentrations showing anti-proliferative activity in cell culture (20 and 40 µM), significant increases in choline containing metabolites were observed in the 1H NMR spectra of the same intact cells. In vivo experiments in nude mice bearing tumors derived from implanted C6 glioma cells, showed that reduction of tumor volume was associated with significant changes in the metabolic profile of the same intact tumor tissues; and were similar to those observed in cell culture. Specifically, the activity of the compounds is mainly associated with an increase in choline and phosphocholine, in both the cell cultures and tumoral tissues. Taurine, a metabolite that has been considered a biomarker of apoptosis, correlated with the reduction of tumor volume. Thus, the results indicate that the mode of action of the glycoside involves, at least in part, alteration of phospholipid metabolism, resulting in cell death.
Highlights
The strategy of applying analytical chemistry methods to monitor anti-cancer therapy effects is based on the principle that the interaction of drugs with cells and tissues affects the network of metabolic pathways occurring within cells
The assignment of relevant, intense and resolved signals was based on the chemical shifts and known multiplicities reported for metabolites of cultured glioma cell lines [11,15], and is illustrated and indicated in a representative spectrum (Figure 2A)
The three peaks present in the 3.23 ppm region were assigned to the total choline trimethyl resonance, –N(CH3)3, and consists of at least three main choline subspecies which were differentiated in the HR spectra: choline, phosphocholine and glycerophophocholine at 3.206, 3.223 and 3.231 ppm respectively (Figure 2)
Summary
The strategy of applying analytical chemistry methods to monitor anti-cancer therapy effects is based on the principle that the interaction of drugs with cells and tissues affects the network of metabolic pathways occurring within cells This interaction could change the concentration of metabolites associated with the altered pathway and proton high resolution (1H HR) NMR spectroscopy offers the possibility of acquiring a snapshot of the sample chemistry, providing, in a single measurement, qualitative and quantitative information of hundreds of metabolites. Analysis of intact tissue using 1H HR magic angle spinning (MAS) NMR spectroscopy provides spectra with high resolution and requires minimal sample preparation, allowing the observation of tissue metabolites in their native state [2,3]. The comparison of the results of NMR spectroscopy studies of cell cultures and tumor biopsies facilitates the correlative interpretation of in vitro and in vivo drug activity, and allows evaluation of the suitability and limitations of each model system
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