Apigenin induces apoptosis via tumor necrosis factor receptor- and Bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin

• Published in: Biochimica et biophysica acta Vol. 1820; no. 7; pp. 1081 - 1091
• Main Authors: Chan, Leong-Perng, Chou, Tzung-Han, Ding, Hsiou-Yu, Chen, Pin-Ru, Chiang, Feng-Yu, Kuo, Po-Lin, Liang, Chia-Hua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2012
• Subjects: 5-Fluorouracil; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; antioxidant activity; antioxidants; Apigenin; Apigenin - pharmacology; apoptosis; Apoptosis - drug effects; Blotting, Western; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; caspases; Caspases - genetics; Caspases - metabolism; cell cycle checkpoints; Cell Cycle Checkpoints - drug effects; cell proliferation; Cell Survival - drug effects; cell viability; Cells, Cultured; chemoprevention; Cisplatin; Cisplatin - administration & dosage; death; Death receptor; Drug Synergism; Flow Cytometry; fluorouracil; Fluorouracil - administration & dosage; glutathione; head; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Human head and neck squamous cell carcinoma; Humans; lipid peroxidation; Lipid Peroxidation - drug effects; liver; Liver - cytology; Liver - drug effects; Liver - metabolism; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mice; oxidative stress; protective effect; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; signal transduction; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; synergism; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; tumor necrosis factors; NF-κB; TRAIL-R; 5-Fluorouracil; TNF-R; Apigenin; HNSCC; Death receptor; ROS; Human head and neck squamous cell carcinoma; EGFR; Cisplatin; 5-Fu
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.04.013

Apigenin, a natural plant flavone, may have chemopreventive and therapeutic potentials for anti-inflammatory, antioxidant, and anti-cancer. Nevertheless, the anti-tumor effect of apigenin on human head and neck squamous cell carcinoma (HNSCC) is not fully understood. The antioxidant capacity and protective effects of apigenin against oxidative stress in murine normal embryonic liver BNLCL2 cells are examined. Cell viability, morphologic change, clonogenic survival, cell cycle distribution, reactive oxygen species (ROS) production, glutathione formation, and death receptors- and Bcl-2-mediated caspase pathways of HNSCC SCC25 cells and A431 cells with apigenin are investigated. Apigenin inhibits the growth of SCC25 and A431 cells and induces cell cycle arrest in the G2/M phase. Apigenin has an antioxidant capacity as well as the ability to inhibit lipid peroxidation. It protects BNLCL2 cells against oxidative damage, and is potentially able to prevent cancer. Apigenin increases intracellular ROS levels and reduces levels of glutathione; it also induces cell apoptosis via tumor necrosis factor receptor (TNF-R)-, TNF-related apoptosis-inducing ligand receptor (TRAIL-R)-, and Bcl-2-mediated caspase-dependent cell death pathways in SCC25 cells. The combination of apigenin with 5-fluorouracil (5-Fu) or cisplatin induces the dramatic death of SCC25 cells. Apigenin induces SCC25 cell apoptosis via the up-regulation of both TNF-R and TRAIL-R signaling pathways, and has a synergistic effect on the inhibition of cell proliferation in combination with 5-Fu or cisplatin. These analytical findings suggest that apigenin may be a good therapeutic agent against HNSCC cells. Apigenin induced SCC25 cell apoptosis via up-regulation of both TNF-R and TRAIL-R signaling pathways, down-regulated Bcl-2, activated caspase-3, and showed synergistic effect on inhibiting cell proliferation as combination with 5-Fu or cisplatin. [Display omitted] ► Apigenin protected BNLCL2 cells against oxidative damage. ► Apigenin induced HNSCC cell apoptosis via TNF-R and TRAIL-R signaling pathways. ► Apigenin induced cell apoptosis by generating oxidative stress. ► The combinatory use of apigenin with 5-Fu or cisplatin accelerated apoptotic cell death.