TY - JOUR T1 - LYG-202 Augments Tumor Necrosis Factor-α-induced Apoptosis Via Attenuating CK2-dependent Nuclear Factor-κB Pathway in HepG2 Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.079848 SP - mol.112.079848 AU - Feihong Chen AU - Na Lu AU - Haiwei Zhang AU - Li Zhao AU - Licheng He AU - Haopeng Sun AU - Qidong You AU - Zhiyu Li AU - Qinglong Guo Y1 - 2012/08/21 UR - http://molpharm.aspetjournals.org/content/early/2012/08/21/mol.112.079848.abstract N2 - Tumor necrosis factor-alpha (TNF-α) is being used as an antineoplastic agent in treatment regimens of patients with locally advanced solid tumors, but TNF-α alone is only marginally active. Clinically, it is usually combined with other chemical agents to increase its tumor response rate. Our previous studies reported that LYG-202, a synthesized flavonoid with a piperazine substitution, has anti-proliferative, anti-angiogenic and pro-apoptotic activities in multiple cancer cell lines. Here we evaluated the anti-neoplastic effect of TNF-α and analyzed the mechanism underlying its combination with LYG-202. Our results indicated that LYG-202 significantly increased the cytostatic and pro-apoptotic activity of TNF-α in HepG2 cells, and heightened the protein level of apoptosis-related genes including caspase-3, 8/9, cleaved PARP and Bid. The facts that LYG-202 had a similar fitness score with CK2 inhibitor CX-4945 implied us it may serve as a potential candidate of CK2 inhibitor, and the kinase activity assay suggested that LYG-202 significantly inhibited CK2 activity. Moreover, the EMSA and luciferase assays showed that LYG-202 blocked TNF-α-induced NF-κB survival signaling pathway primarily by inactivating protein kinase CK2. In murine xenograft models, we also found that LYG-202 enhanced TNF-α antineoplastic activity, inhibited CK2 activity and NF-κB-regulated anti-apoptotic gene expression. All these results showed that LYG-202 enhanced TNF-α-induced apoptosis by attenuating CK2-dependent NF-κB pathway, and probably served as a most promising agent in combination with TNF-α. ER -