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: Jin Ding, Wen Wen, Daimin Xiang, Peipei Yin, Yanfang Liu, Chang Liu, Guoping He, Zhuo Cheng, Jianpeng Yin, Chunquan Sheng, Wen Zhang, Fajun Nan, Wencai Ye, Xiuli Zhang, Hongyang Wang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 11627-39 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25890498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Bufanolides
• Protein Kinase Inhibitors
• SOX2 protein, human
• SOXB1 Transcription Factors
• bufarenogin
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Binding Sites
• Bufanolides (chemistry, metabolism, pharmacology)
• Carcinoma, Hepatocellular (drug therapy, enzymology, genetics, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• ErbB Receptors (antagonists & inhibitors, chemistry, metabolism)
• HCT116 Cells
• HeLa Cells
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, enzymology, genetics, pathology)
• Mice, Nude
• Molecular Docking Simulation
• Neoplastic Stem Cells (drug effects, metabolism)
• Protein Binding
• Protein Kinase Inhibitors (chemistry, metabolism, pharmacology)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, chemistry, genetics, metabolism)
• SOXB1 Transcription Factors (genetics, metabolism)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Time Factors
• Transfection
• Tumor Burden
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays