Preferential inhibition of hepatocellular carcinoma by the flavonoid             Baicalein through blocking MEK-ERK signaling.
Baicalein is a purified flavonoid extracted from the roots of Scutellaria baicalensis or Scutellaria radix. Although previous studies have suggested that Baicalein possesses an in vitro anti-hepatocellular carcinoma activity, its in vivo effects and mechanisms of action are still not completely understood. In this study, Baicalein at concentrations of 40-120 µM exhibited significant cytotoxicity to three hepatocellular carcinoma (HCC) cell lines but marginal cytotoxicity to a normal liver cell line in vitro. Compared to a standard chemotherapy drug, 5-fluorouracil (5-FU), Baicalein had greater effect on HCC cells but less toxicity on normal liver cells. Treatment with Baicalein dramatically reduced mitochondrial transmembrane potential, and activated caspase-9 and caspase-3. Blockade of Baicalein-induced apoptosis with a pan-caspase inhibitor partially attenuated Baicalein-induced growth inhibition in HCC. Baicalein treatment significantly inhibited tumor growth of HCC xenografts in mice. Induction of apoptosis was demonstrated in Baicalein-treated xenograft tumors by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Furthermore, Baicalein treatment dramatically decreased the levels of phosphorylation of MEK1, ERK1/2 and Bad in vitro and in vivo. Overexpression of human MEK1 partially blocked Baicalein-induced growth inhibition. Consequently, these findings suggest that Baicalein preferentially inhibits HCC tumor growth through inhibition of MEK-ERK signaling and by inducing intrinsic apoptosis.
Department of General Surgery, Second Affiliated Hospital, School                     of Medicine, Xi'an Jiaotong University, Xi'an 710004, P.R. China.
Rong-Rui
RR
Liang
Shu
S
Zhang
Jun-An
JA
Qi
Zhi-Dong
ZD
Wang
Jun
J
Li
Pei-Jun
PJ
Liu
Chen
C
Huang
Xiao-Feng
XF
Le
Jun
J
Yang
Zong-Fang
ZF
Li
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D053148:Caspase 3 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D053453:Caspase 9 / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D044950:Flavanones / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation; D010936:Plant Extracts; D031364:Scutellaria baicalensis
D004791:Enzyme Inhibitors; D044950:Flavanones; D010936:Plant Extracts; C499814:Scutellaria baicalensis extract; C006680:baicalein; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053453:Caspase 9; D005472:Fluorouracil