title: ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling.
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.
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|National Center for Liver Cancer, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|National Center for Liver Cancer, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|National Center for Liver Cancer, Shanghai, China.
authors.forename: Daimin
authors.initials: D
authors.lastname: Xiang
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Yin
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: He
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: National Center for Drug Screen, Shanghai, China.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Yin
authors.affiliation: College of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.affiliation: College of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: National Center for Drug Screen, Shanghai, China.
authors.forename: Fajun
authors.initials: F
authors.lastname: Nan
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Wencai
authors.initials: W
authors.lastname: Ye
authors.affiliation: Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|National Center for Liver Cancer, Shanghai, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002018:Bufanolides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D047428:Protein Kinase Inhibitors; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C006835:bufarenogin; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: epithelial growth factor receptor; hepatocellular carcinoma; hepatocyte growth factor receptor; ψ-Bufarenogin