A Potent Inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen Activated Protein (MAP) Kinase Signalling, Quercetin (3, 3', 4', 5, 7-Pentahydroxyflavone) Promotes Cell Death in Ultraviolet (UV)-B-Irradiated B16F10 Melanoma Cells

• Published in: PloS one 2015-07, Vol.10 (7), p.e0131253
• Main Authors: Rafiq, Rather A, Quadri, Afnan, Nazir, Lone A, Peerzada, Kaiser, Ganai, Bashir A, Tasduq, Sheikh A
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenosine diphosphate; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis Inducing Factor - metabolism; Apoptosis-inducing factor; BAX protein; Bcl-2 protein; BIM protein; Calcium; Calcium - metabolism; Calcium homeostasis; Caspase; Caspases - metabolism; Cell death; Cell Death - drug effects; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Cleavage; Deoxyribonucleic acid; Depolarization; Diet; DNA; Enzyme inhibitors; Extracellular signal-regulated kinase; G1 Phase - drug effects; Homeostasis; Humans; Inhibitors; Kinases; Lymphocytes B; Melanoma; Melanoma - metabolism; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondria; Mitogen-Activated Protein Kinases - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB protein; Oxidizing agents; Oxygen; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Poly(ADP-ribose) polymerase; Quercetin - pharmacology; Radiation; Radiation damage; Reactive oxygen species; Reactive Oxygen Species - metabolism; Ribose; Signal transduction; Signal Transduction - drug effects; Signaling; Skin cancer; Skin diseases; Translocation; Ultraviolet radiation; Ultraviolet Rays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0131253

Ultraviolet (UV) radiation-induced skin damage contributes strongly to the formation of melanoma, a highly lethal form of skin cancer. Quercetin (Qu), the most widely consumed dietary bioflavonoid and well known inhibitor of phosphoinositide 3-kinase (PI3K) and mitogen activated protein (MAP) kinase signalling, has been reported to be chemopreventive in several forms of non-melanoma skin cancers. Here, we report that the treatment of ultraviolet (UV)-B-irradiated B16F10 melanoma cells with quercetin resulted in a dose dependent reduction in cell viability and increased apoptosis. The present study has brought out that the pro-apoptotic effects of quercetin in UVB-irradiated B16F10 cells are mediated through the elevation of intracellular reactive oxygen species (ROS) formation, calcium homeostasis imbalance, modulation of anti-oxidant defence response and depolarization of mitochondrial membrane potential (ΔΨM). Promotion of UVB-induced cell death by quercetin was further revealed by cleavage of chromosomal DNA, caspase activation, poly (ADP) ribose polymerase (PARP) cleavage, and an increase in sub-G1 cells. Quercetin markedly attenuated MEK-ERK signalling, influenced PI3K/Akt pathway, and potentially enhanced the UVB-induced NF-κB nuclear translocation. Furthermore, combined UVB and quercetin treatment decreased the ratio of Bcl-2 to that of Bax, and upregulated the expression of Bim and apoptosis inducing factor (AIF). Overall, these results suggest the possibility of using quercetin in combination with UVB as a possible treatment option for melanoma in future.