Quercetin Induces Mitochondrial Mediated Apoptosis and Protective Autophagy in Human Glioblastoma U373MG Cells

Abstract

Quercetin is a dietary flavonoid with known antitumor effects against several types of cancers by promoting apoptotic cell death and inducing cell cycle arrest. However, U373MG malignant glioma cells expressing mutant p53 are resistant to a 24 h quercetin treatment. In this study, the anticancer effect of quercetin was reevaluated in U373MG cells, and quercetin was found to be significantly effective in inhibiting proliferation of U373MG cells in a concentration-dependent manner after 48 and 72 h of incubation. Quercetin induced U373MG cell death through apoptosis, as evidenced by the increased number of cells in the sub-G1 phase, the appearance of fragmented nuclei, decreased mitochondrial membrane potential, proteolytic activation of caspase-3 and caspase-7, an increase in caspase-3 and 9 activities, and degradation of poly(ADP-ribose) polymerase protein. Furthermore, quercetin activated JNK and increased the expression of p53, which translocated to the mitochondria and simultaneously led to the release of cytochrome c from mitochondria to the cytosol. We also found that quercetin induced autophagy. Pretreatment with chloroquine, an autophagy inhibitor, strongly augmented apoptosis in U373MG cells, indicating that quercetin induced protective autopagy in U373MG cells.

Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells

“…In addition, treatment with melatonin also reduces autophagy in the liver of ob/ob mice, or in morphine‐treated rat neurons , and in both cases, autophagy reduction is beneficial. Therefore, melatonin modulation of autophagy seems to be cell‐type‐ and context‐dependent, similar to other antioxidant molecules with analog properties .…”

Hypoxia Promotes Synergy between Mitomycin C and Bortezomib through a Coordinated Process of Bcl-xL Phosphorylation and Mitochondrial Translocation of p53

“…Death signals have been reported to be able to induce p53 translocation to the mitochondria via the transcription-independent apoptotic signal (35–38). p53 participates directly in the intrinsic apoptosis pathway by interacting with the multidomain members of the Bcl-2 family to induce mitochondrial outer membrane permeabilization, regardless of several common mutations (39–41). In the present studies, we observed that for mitomycin C, the combinatorial treatment, as well as hypoxic conditions, induced translocation of p53 protein to the mitochondria, while the application of bortezomib had a limited effect on p53 elevation and mitochondrial translocation.…”

Therapeutic Strategies for Mitochondrial Disorders

“…In U373MG malignant glioma cells quercetin induced mitochondrial apoptosis via cytochrome-c release and accumulation of reactive oxygen species as evidenced by more cells in the sub-G1 phase, the appearance of fragmented nuclei, decreased mitochondrial membrane potential, activation of caspase-3 and caspase-7, and degradation of the poly(adenosine di-phosphate-ribose) polymerase protein. 67 In these cell cultures, quercetin also induced protective autophagy.…”