PMID- 22909797
OWN - NLM
STAT- MEDLINE
DCOM- 20130212
LR  - 20161125
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Linking)
VI  - 82
IP  - 5
DP  - 2012 Nov
TI  - LYG-202 augments tumor necrosis factor-alpha-induced apoptosis via attenuating casein 
      kinase 2-dependent nuclear factor-kappaB pathway in HepG2 cells.
PG  - 958-71
LID - 10.1124/mol.112.079848 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha) is being used as an antineoplastic agent in 
      treatment regimens of patients with locally advanced solid tumors, but TNF-alpha 
      alone is only marginally active. In clinical use, it is usually combined with 
      other chemical agents to increase its tumor response rate. Our previous studies 
      reported that LYG-202 
      (5-hydroxy-8-methoxy-7-(4-(4-methylpiperazin-1-yl)butoxy)-2-phenyl-4H-chromen-4-one), 
      a synthesized flavonoid with a piperazine substitution, has antiproliferative, 
      antiangiogenic, and proapoptotic activities in multiple cancer cell lines. Here 
      we evaluated the antineoplastic effect of TNF-alpha and analyzed the mechanism 
      underlying its combination with LYG-202. Our results indicated that LYG-202 
      significantly increased the cytostatic and proapoptotic activity of TNF-alpha in 
      HepG2 cells and heightened the protein level of apoptosis-related genes including 
      caspase-3, caspase-8/9, cleaved poly(ADP-ribose) polymerase, and Bid. The fact 
      that LYG-202 had a fitness score similar to that of the casein kinase 2 (CK2) 
      inhibitor naphthyridine-8-carboxylate (CX-4945) implied to us that it may serve 
      as a potential candidate for CK2 inhibitor, and the kinase activity assay 
      suggested that LYG-202 significantly inhibited CK2 activity. Moreover, the 
      electrophoretic mobility shift assay and luciferase assay showed that LYG-202 
      blocked the TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) survival signaling pathway 
      primarily by inactivating protein kinase CK2. In murine xenograft models, we also 
      found that LYG-202 enhanced TNF-alpha antineoplastic activity and inhibited CK2 
      activity and NF-kappaB-regulated antiapoptotic gene expression. All these results 
      showed that LYG-202 enhanced TNF-alpha-induced apoptosis by attenuating the 
      CK2-dependent NF-kappaB pathway and probably is a promising agent in combination with 
      TNF-alpha.
FAU - Chen, Fei-hong
AU  - Chen FH
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China.
FAU - Lu, Na
AU  - Lu N
FAU - Zhang, Hai-wei
AU  - Zhang HW
FAU - Zhao, Li
AU  - Zhao L
FAU - He, Li-cheng
AU  - He LC
FAU - Sun, Hao-peng
AU  - Sun HP
FAU - You, Qi-dong
AU  - You QD
FAU - Li, Zhi-yu
AU  - Li ZY
FAU - Guo, Qing-long
AU  - Guo QL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120821
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Flavones)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (LYG 202)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Nfkbia protein, mouse)
RN  - 0 (Piperazines)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.11.1 (Casein Kinase II)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Casein Kinase II/*physiology
MH  - Caspases/metabolism
MH  - Cell Nucleus/metabolism
MH  - Cell Proliferation/drug effects
MH  - Drug Synergism
MH  - Electrophoretic Mobility Shift Assay
MH  - Flavones/*pharmacology
MH  - Genes, Reporter
MH  - Hep G2 Cells
MH  - Humans
MH  - I-kappa B Kinase/antagonists & inhibitors
MH  - I-kappa B Proteins/metabolism
MH  - Luciferases/genetics
MH  - Male
MH  - Mice
MH  - Molecular Docking Simulation
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/genetics/*physiology
MH  - Phosphorylation
MH  - Piperazines/*pharmacology
MH  - Signal Transduction
MH  - Transcription Factor RelA/metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/08/23 06:00
MHDA- 2013/02/13 06:00
CRDT- 2012/08/23 06:00
PHST- 2012/08/23 06:00 [entrez]
PHST- 2012/08/23 06:00 [pubmed]
PHST- 2013/02/13 06:00 [medline]
AID - mol.112.079848 [pii]
AID - 10.1124/mol.112.079848 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2012 Nov;82(5):958-71. doi: 10.1124/mol.112.079848. Epub 2012 Aug 
      21.