Effects of quercetin nanoliposomes on C6 glioma cells through induction of type III programmed cell death

Abstract

Background:Quercetin has been shown to induce apoptosis in a number of cancer cell lines, but a quercetin-loaded nanoliposomal formulation with enhanced antitumor activity in C6 glioma cells and its effect on cancer cell death has not been well studied. The aim of this study was to examine if quercetin-loaded liposomes (QUE-NL) has enhanced cytotoxic effects and if such effects involve type III programmed cell death in C6 glioma cells. Methods: C6 glioma cells were treated with QUE-NL and assayed for cell survival, apoptosis, and necrosis. Levels of reactive oxygen species production and loss of mitochondrial membrane potential (∆Ψm) were also determined by flow cytometry assay to assess the effects of QUE-NL. ATP levels and lactate dehydrogenase activity were measured, and Western blotting was used to assay cytochrome C release and caspase expression. Results: QUE-NL induced type III (necrotic) programmed cell death in C6 glioma cells in a dose-dependent and time-dependent manner. High concentrations of QUE-NL induced cell necrosis, which is distinct from apoptosis and autophagy, whereas liposomes administered alone induced neither significant apoptosis nor necrosis in C6 glioma cells. QUE-NL-induced ∆Ψm loss and cytochrome C release had no effect on caspase activation, but decreased ATP levels and increased lactate dehydrogenase activity indicated that QUE-NL stimulated necrotic cell death. Conclusion: C6 glioma cells treated with QUE-NL showed a cellular pattern associated with necrosis without apoptosis and was independent of caspase activity. Nonapoptotic cell death induced by high concentrations of QUE-NL for controlling caspase-independent type III programmed cell death may provide the basis for novel therapeutic approaches to overcome avoidance of apoptosis by malignant cells.

The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death

“…We then examined the phosphorylation of JAK2, which has been reported to correlate with cell death induction, using western blotting. 12 The dynamic activation of JAK2 was observed 12–24 h after QUE-NL treatment. We therefore presumed that JAK2 was involved in QUE-NL-induced C6 glioma cell death.…”

“…Moreover, treatment with QUE-NLs resulted in necrotic cell death, because it did not trigger the activation of caspases from the mitochondrial pathway. 12 QUE-NL-induced necrotic cell death was partially reversible by pretreatment with AG490, a JAK2 (Janus kinase 2) specific inhibitor. 13 Paradoxically, AG490 effectively enhanced the effects of QUE-NL-induced apoptosis.…”

Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals

“…Oral administration of 30 mg/kg of free and nano-quercetin three times per week at week 3, 4, 5 post tumor inoculation to A549 lung tumor xenograft mice decreased the tumor size 20% and 40%, respectively, but they did not change animal body weight [105]. Wang G et al demonstrated that quercetin nanoliposomes decreased the viability of C6 glioma cells, and induced necrotic death of those cells [118]. Dhawan S et al found that the intravenous administration of quercetin improved memory retention and increased brain antioxidant capacity in rats with aluminium-induced dementia, and quercetin encapsulated SLNs significantly improved those beneficial effects by more than two-fold [119].…”

Rutin, quercetin, and free amino acid analysis in buckwheat (Fagopyrum) seeds from different locations

“…Quercetin is an important factor for plant secondary metabolism; it has a wide range of biological activity and is also a promising candidate for prevention and treatment of various cancers (Joanna et al, 2011;Wang et al, 2012). The quercetin glycosides and free quercetin in buckwheat flowers, leaves, stems, and achenes were discovered by Dadakova in 2010.…”