Frontiers in Cell and Developmental Biology (Jul 2021)

Probing Synergistic Targets by Natural Compounds for Hepatocellular Carcinoma

  • Jian Gao,
  • Zuojing Yin,
  • Zhuanbin Wu,
  • Zhen Sheng,
  • Chao Ma,
  • Rui Chen,
  • Xiongwen Zhang,
  • Kailin Tang,
  • Jian Fei,
  • Zhiwei Cao

DOI
https://doi.org/10.3389/fcell.2021.715762
Journal volume & issue
Vol. 9

Abstract

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BackgroundDesigning combination drugs for malignant cancers has been restricted due to the scarcity of synergy-medicated targets, while some natural compounds have demonstrated potential to enhance anticancer effects.MethodsWe here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity coinhibited during the synergistic cytotoxicity induction in BEL-7402 cells. Then, selective coinhibitors of NF-κB and c-JUN were tested demonstrating similar synergistic antiproliferation activity.ResultsConsistent with in vivo experiments of zebrafish, coinhibitors were found to significantly reduce tumor growth by 79% and metastasis by 96% compared to blank control, accompanied by anti-angiogenic activity. In an analysis of 365 HCC individuals, the low expression group showed significantly lower malignancies and better prognosis, with the median survival time increased from 67 to 213%, compared to the rest of the groups.ConclusionTogether, NF-κB and c-JUN were identified as promising synergistic inducers in developing anti-HCC therapies. Also, our method may provide a feasible strategy to explore new targeting space from natural compounds, opening opportunities for the rational design of combinational formulations in combatting malignant cancers.

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