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Published on: September 12, 2019
Probing Synergistic Targets by Natural Compounds for Hepatocellular Carcinoma
Jian Gao1, Zuojing Yin1, Zhuanbin Wu2
1Department of Gastroenterology, School of Life Sciences and Technology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
Background:
Designing 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.
Methods:
We 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.
Results:
Consistent 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.
Conclusion:
Together, 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.
Insights
Berberine and Evodiamine synergistically target NF-κB and c-JUN in hepatocellular carcinoma (HCC). This approach significantly reduces tumor growth and metastasis, offering a new strategy for combination cancer therapies.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Designing combination cancer drugs is challenging due to limited synergy targets.
- Natural compounds show promise in enhancing anticancer effects.
Purpose of the Study:
- To explore synergy-mediated targets using Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC).
- To identify key molecular targets for synergistic drug combinations in HCC treatment.
Main Methods:
- Genomics-derived HCC signaling networks were used to identify targets.
- NF-κB and c-JUN were identified as key responding elements with coinhibited transcriptional activity.
- Selective coinhibitors of NF-κB and c-JUN were tested for synergistic antiproliferation activity.
Main Results:
- Coinhibitors significantly reduced tumor growth by 79% and metastasis by 96% in zebrafish models.
- Anti-angiogenic activity was observed.
- In HCC patients, low expression of identified targets correlated with reduced malignancy and improved prognosis (median survival increased by 67-213%).
Conclusions:
- NF-κB and c-JUN are promising synergistic targets for anti-HCC therapies.
- This method offers a strategy to discover new therapeutic targets from natural compounds.
- Opens opportunities for rational design of combination therapies for cancers.
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