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ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling.
Oncotarget. 2015 May 10; 6(13):11627-39.O

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+Show Affiliations

The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. National Center for Liver Cancer, Shanghai, China.The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. National Center for Liver Cancer, Shanghai, China.The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. National Center for Liver Cancer, Shanghai, China.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.Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.Department of Pharmacology, Shanghai Institute of Pharmaceutical Industry, Shanghai, China.The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.National Center for Drug Screen, Shanghai, China.College of Pharmacy, Second Military Medical University, Shanghai, China.College of Pharmacy, Second Military Medical University, Shanghai, China.National Center for Drug Screen, Shanghai, China.College of Pharmacy, Jinan University, Guangzhou, China.Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. National Center for Liver Cancer, Shanghai, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25890498

Citation

Ding, Jin, et al. "Ψ-Bufarenogin, a Novel Anti-tumor Compound, Suppresses Liver Cancer Growth By Inhibiting Receptor Tyrosine Kinase-mediated Signaling." Oncotarget, vol. 6, no. 13, 2015, pp. 11627-39.
Ding J, Wen W, Xiang D, et al. Ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling. Oncotarget. 2015;6(13):11627-39.
Ding, J., Wen, W., Xiang, D., Yin, P., Liu, Y., Liu, C., He, G., Cheng, Z., Yin, J., Sheng, C., Zhang, W., Nan, F., Ye, W., Zhang, X., & Wang, H. (2015). Ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling. Oncotarget, 6(13), 11627-39.
Ding J, et al. Ψ-Bufarenogin, a Novel Anti-tumor Compound, Suppresses Liver Cancer Growth By Inhibiting Receptor Tyrosine Kinase-mediated Signaling. Oncotarget. 2015 May 10;6(13):11627-39. PubMed PMID: 25890498.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling. AU - Ding,Jin, AU - Wen,Wen, AU - Xiang,Daimin, AU - Yin,Peipei, AU - Liu,Yanfang, AU - Liu,Chang, AU - He,Guoping, AU - Cheng,Zhuo, AU - Yin,Jianpeng, AU - Sheng,Chunquan, AU - Zhang,Wen, AU - Nan,Fajun, AU - Ye,Wencai, AU - Zhang,Xiuli, AU - Wang,Hongyang, PY - 2015/02/05/received PY - 2015/02/23/accepted PY - 2015/4/20/entrez PY - 2015/4/22/pubmed PY - 2016/3/2/medline KW - epithelial growth factor receptor KW - hepatocellular carcinoma KW - hepatocyte growth factor receptor KW - ψ-Bufarenogin SP - 11627 EP - 39 JF - Oncotarget JO - Oncotarget VL - 6 IS - 13 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/25890498/ψ_Bufarenogin_a_novel_anti_tumor_compound_suppresses_liver_cancer_growth_by_inhibiting_receptor_tyrosine_kinase_mediated_signaling_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=3435 DB - PRIME DP - Unbound Medicine ER -