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Title: $ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling
Abstract: // Jin Ding 1, 7, * , Wen Wen 1, 7, * , Daimin Xiang 1, 7, * , Peipei Yin 1, 2 , Yanfang Liu 3 , Chang Liu 2 , Guoping He 1 , Zhuo Cheng 1 , Jianpeng Yin 5 , Chunquan Sheng 4 , Wen Zhang 4 , Fajun Nan 5 , Wencai Ye 6 , Xiuli Zhang 3 , Hongyang Wang 1, 7 1 The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 2 Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai, China 3 Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China 4 College of Pharmacy, Second Military Medical University, Shanghai, China 5 National Center for Drug Screen, Shanghai, China 6 College of Pharmacy, Jinan University, Guangzhou, China 7 National Center for Liver Cancer, Shanghai, China * These authors have contributed equally to this work Correspondence to: Hongyang Wang, e-mail: hywangk@vip.sina.com Jin Ding, e-mail: dingjin1103@163.com 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 ABSTRACT 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.