Underlying Mechanism of Quercetin-induced Cell Death in Human Glioma Cells

Abstract

There has been considerable interest in recent years in the anti-tumor activities of flavonoids. Quercetin, a ubiquitous bioactive flavonoid, can inhibit proliferation and induce apoptosis in a variety of cancer cells. However, the precise molecular mechanism by which quercetin induces apoptosis in cancer cells is poorly understood. The present study was undertaken to examine the effect of quercetin on cell viability and to determine its underlying mechanism in human glioma cells. Quercetin resulted in loss of cell viability in a dose- and time-dependent manner and the decrease in cell viability was mainly attributed to cell death. Quercetin did not increase reactive oxygen species (ROS) generation and the quercetin-induced cell death was also not affected by antioxidants, suggesting that ROS generation is not involved in loss of cell viability. Western blot analysis showed that quercetin treatment caused rapid reduction in phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. Transient transfection with constitutively active forms of MEK and Akt protected against the quercetin-induced loss of cell viability. Quercetin-induced depolarization of mitochondrial membrane potential. Caspase activity was stimulated by quercetin and caspase inhibitors prevented the quercetin-induced loss of cell viability. Quercetin resulted in a decrease in expression of survivin, antiapoptotic proteins. Taken together, these findings suggest that quercetin results in human glioma cell death through caspase-dependent mechanisms involving down-regulation of ERK, Akt, and survivin.

Antiproliferative and pro-apoptotic effects of quercetin on human pancreatic carcinoma cell lines EPP85-181P and EPP85-181RDB.

“…This effect might be linked to strong inhibition of topo II by both compounds [18,42]. The decrease in therapeutic dose of DB may prove important due to the chance for prevention of negative side effects induced by the drug, assuming that Q acts selectively: it inhibits proliferation only in neoplastic cells in parallel protecting normal tissues [13,21,36].…”

“…Q affects directly various type kinases, e.g., protein kinase C, PI 3K, MAPK, ERK, CDK and their respective metabolic pathways, which play a significant role in carcinogenesis [16][17][18][19][20][21]. The studies on effects of carcinogens on normal cells in presence of Q, demonstrated also its antioxidant properties and a protective role against mutagenesis in healthy tissues [2,[22][23][24].…”

Novel Therapeutic Venues for Glioblastoma: Novel Rising Preclinical Treatment Opportunities

“…Other researchers have also confirmed the observation that quercetin might have antiglioma activity. Kim et al found that quercetin induced cell death in human glioma cells (Kim, Choi et al, 2008). Mechanistically, they found that quercetin inhibited the ERK and Akt pathway and that ectopic expression of constitutively active forms of ERK and Akt protected against quercetin mediated cell death in glioma (Kim, Choi et al, 2008).…”

“…Kim et al found that quercetin induced cell death in human glioma cells (Kim, Choi et al, 2008). Mechanistically, they found that quercetin inhibited the ERK and Akt pathway and that ectopic expression of constitutively active forms of ERK and Akt protected against quercetin mediated cell death in glioma (Kim, Choi et al, 2008). Furthermore, the inhibitor of apoptosis protein, survivin, was suppressed in a concentration dependent manner by quercetin (Kim, Choi et al, 2008).…”

“…Mechanistically, they found that quercetin inhibited the ERK and Akt pathway and that ectopic expression of constitutively active forms of ERK and Akt protected against quercetin mediated cell death in glioma (Kim, Choi et al, 2008). Furthermore, the inhibitor of apoptosis protein, survivin, was suppressed in a concentration dependent manner by quercetin (Kim, Choi et al, 2008). Since primary glioblastomas often exhibit loss of PTEN and/or amplification of EGFR, leading to a profound activation of the Akt pathway and possible resulting in an increased expression of survivin as survivin has been shown to be a downstream target of the Akt pathway, quercetin may be a novel welcome contribution in glioma therapy.…”