Abrogation of Akt signaling by Isobavachalcone contributes to its anti-proliferative effects towards human cancer cells.
Akt signaling pathway has attracted much attention as a promising target for cancer therapeutics. Herein, we report that Isobavachalcone (IBC), a natural chalcone, potently abrogates Akt signaling and exerts anti-proliferative effects on several human cancer cell lines. Modeling results from the Sybyl/FlexiDock program suggest that IBC potentially binds to the ATP-binding pocket of Akt, which is confirmed by the observations that IBC inhibits Akt1 kinase in vitro. Further studies reveal that IBC significantly abates Akt phosphorylation at Ser-473 and Akt kinase activity in cells, which subsequently leads to inhibition of Akt downstream substrates and evokes significant levels of apoptosis associated with mitochondria pathway.
Jing
Hui
H
Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Zhou
Xinglu
X
Dong
Xiaowu
X
Cao
Ji
J
Zhu
Hong
H
Lou
Jianshu
J
Hu
Yongzhou
Y
He
Qiaojun
Q
Yang
Bo
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003593:Cytoplasm / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D047188:Chalcones; D017382:Reactive Oxygen Species; C468754:isobavachalcone; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases