Quercetin derivatives as potent inducers of selective cytotoxicity in glioma cells

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Quercetin (Q) is a flavonoid widely distributed in the plant kingdom and well-known for its ability to exert antioxidant, prooxidant and anticarcinogenic activities in several tumor cells. Furthermore, quercetin plays an important role both in the regulation of key elements in cellular signal transduction pathways related to apoptotic cell death, and in cell cycle progression. Several studies have reported of toxic effects of Q against glioma cell lines. In this study, the effects of Q and of some Q-derivatives (acyl esters and bromo-derivatives) on U373-MG and 9L glioma cell lines survival are analyzed. The 24-hour treatment of glioma cells with several concentrations of Q (25, 50 and 100 μM) did not cause any cytotoxic effects, while the administration of Q-derivatives, such as acylated and brominated quercetin, caused a sharp increase in cell death. Among all tested derivatives, 3-O-decanoylquercetin 10 manifested the strongest cytotoxic effect at a concentration as low as 25 μM both in U373-MG (ca. 40% viability after 24 h) and in 9L cells (ca. 20% viability after 24 h). The cytotoxic effects of the Q-derivatives 3 and 10–13 were proven to be satisfactorily selective for glioma cells. When Q-derivatives were in fact administered to mouse primary astroglial or human fibroblast cell cultures, a higher cell survival rate (˜ 90–70% and 55–45%, respectively) was observed relative to that detected in glioma cells. These results prove that selective esterification and bromination of Q increase to a great extent the toxicity of this polyphenol against glioma cells, thereby providing a possible new tool for cyto-specific glioma therapy.

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