Kaempferol induces apoptosis in glioblastoma cells through oxidative stress

Abstract

Despite recent advances in understanding molecular mechanisms involved in glioblastoma progression, the prognosis of the most malignant brain tumor continues to be dismal. Because the flavonoid kaempferol is known to suppress growth of a number of human malignancies, we investigated the effect of kaempferol on human glioblastoma cells. Kaempferol induced apoptosis in glioma cells by elevating intracellular oxidative stress. Heightened oxidative stress was characterized by an increased generation of reactive oxygen species (ROS) accompanied by a decrease in oxidant-scavenging agents such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). Knockdown of SOD-1 and TRX-1 expression by small interfering RNA (siRNA) increased ROS generation and sensitivity of glioma cells to kaempferol-induced apoptosis. Signs of apoptosis included decreased expression of Bcl-2 and altered mitochondrial membrane potential with elevated active caspase-3 and cleaved poly(ADP-ribose) polymerase expression. Plasma membrane potential and membrane fluidity were altered in kaempferol-treated cells. Kaempferol suppressed the expression of proinflammatory cytokine interleukin-6 and chemokines interleukin-8, monocyte chemoattractant protein-1, and regulated on activation, normal T-cell expressed and secreted. Kaempferol inhibited glioma cell migration in a ROS-dependent manner. Importantly, kaempferol potentiated the toxic effect of chemotherapeutic agent doxorubicin by amplifying ROS toxicity and decreasing the efflux of doxorubicin. Because the toxic effect of both kaempferol and doxorubicin was amplified when used in combination, this study raises the possibility of combinatorial therapy whose basis constitutes enhancing redox perturbation as a strategy to kill glioma cells. [Mol Cancer Ther 2007;6(9):2544 -53]

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

“…In addition to GSH, catalase and SOD play important role to detoxify hydrogen peroxide and super-oxides, respectively. A number of therapeutic agents have been shown to increase intracellular ROS generation by downregulating antioxidant enzymes such as catalase and SOD (7,20,23). However, some other studies have reported that reduction in intracellular GSH is necessary for the formation of ROS (10,24).…”

“…ROS are produced by eukaryotic cells during normal oxidative metabolism and cells' antioxidant system scavenges ROS to maintain the redox balance. However, an imbalance between production of ROS and cells antioxidant system's ability to readily detoxify ROS results in oxidative stress (6,7). Glutathione (GSH) is the most abundant intracellular antioxidant involved in the protection of cells against oxidative damage and in various detoxification mechanisms (8)(9)(10).…”

Antiproliferative and Apoptosis Inducing Effects of Non-Polar Fractions from Lawsonia inermis L. in Cervical (HeLa) Cancer Cells

“…In response to ROS, mitochondrial membrane become permeable leading to the release of cytochrome c which induces caspases cascades ultimately resulting in apoptosis (Conklin 2004;Circu and Aw 2010;Simon et al 2000;Thayyullathil et al 2008). Sharma et al (2007) reported that Kaempferol showed apoptogenic activity in human glioblastoma cells by elevating the levels of ROS. Ellagic acid caused apoptosis of tsgh8301 human bladder cancer cells (Ho et al 2014).…”

Kaempferol modulates the metastasis of human non-small cell lung cancer cells by inhibiting epithelial-mesenchymal transition

“…Kaempferol, is a member of the flavonoid family and exhibits potential anti-tumor activities. Previous studies demons -trated that kaempferol inhibits growth and proliferation of cancer cells by various mechanisms including apoptosis (Sharma et al, 2007) cell cycle arrest (Cho et al, 2013) and inhibition of tyrosine phosphorylation (Lee et al, 1998). However, studies focusing on the potential of kaempferol in overcoming invasiveness of cancer cells particularly lung cancer have rarely been done.…”