ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling
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Jin Ding1,7,*, Wen Wen1,7,*, Daimin Xiang1,7,*, Peipei Yin1,2, Yanfang Liu3, Chang Liu2, Guoping He1, Zhuo Cheng1, Jianpeng Yin5, Chunquan Sheng4, Wen Zhang4, Fajun Nan5, Wencai Ye6, Xiuli Zhang3, Hongyang Wang1,7
1The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
2Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai, China
3Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
4College of Pharmacy, Second Military Medical University, Shanghai, China
5National Center for Drug Screen, Shanghai, China
6College of Pharmacy, Jinan University, Guangzhou, China
7National Center for Liver Cancer, Shanghai, China
*These authors have contributed equally to this work
Hongyang Wang, e-mail: [email protected]
Jin Ding, e-mail: [email protected]
Keywords: ψ-Bufarenogin, hepatocellular carcinoma, epithelial growth factor receptor, hepatocyte growth factor receptor
Received: February 05, 2015 Accepted: February 23, 2015 Published: March 23, 2015
Resistance of hepatocellular carcinoma (HCC) to existing chemotherapeutic agents largely contributes to the poor prognosis of patients, and discovery of novel anti-HCC drug is in an urgent need. Herein we report ψ-Bufarenogin, a novel active compound that we isolated from the extract of toad skin, exhibited potent therapeutic effect in xenografted human hepatoma without notable side effects. In vitro, ψ-Bufarenogin suppressed HCC cells proliferation through impeding cell cycle progression, and it facilitated cell apoptosis by downregulating Mcl-1 expression. Moreover, ψ-Bufarenogin decreased the number of hepatoma stem cells through Sox2 depression and exhibited synergistic effect with conventional chemotherapeutics. Mechanistic study revealed that ψ-Bufarenogin impaired the activation of MEK/ERK pathway, which is essential in the proliferation of hepatoma cells. ψ-Bufarenogin notably suppressed PI3-K/Akt cascade, which was required in ψ-Bufarenogin-mediated reduction of Mcl-1 and Sox2. ψ-Bufarenogin inhibited the auto-phosphorylation and activation of epithelial growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), thereafter suppressed their primary downstream cascades Raf/MEK/ERK and PI3-K/Akt signaling. Taken together, ψ-Bufarenogin suppressed HCC growth via inhibiting, at least partially, receptor tyrosine kinases-regulated signaling, suggesting that ψ-Bufarenogin could be a novel lead compound for anti-HCC drug.
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