Abstract
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.
Highlights
Characterized by high heterogeneity, rapid development, and early metastasis, hepatocellular carcinoma (HCC) has been referred to as the leading cause of cancer-related death worldwide with the majority of cases found in the Asia-Pacific region (Yang et al, 2019)
BER was dissolved in sterile saline, and EVO was dissolved in methyl sulfoxide (DMSO) at 0.01 mol/L to make the stock solution
Based on previous studies (Yang and Huang, 2013; Zhao et al, 2020), BER and EVO were illustrated as a pair of natural probes to evaluate the feasibility of identifying synergistic targets in BEL-7402
Summary
Characterized by high heterogeneity, rapid development, and early metastasis, hepatocellular carcinoma (HCC) has been referred to as the leading cause of cancer-related death worldwide with the majority of cases found in the Asia-Pacific region (Yang et al, 2019). Only a few inhibitors of sorafenib, lenvatinib (firstline), and regorafenib (second-line) were clinically approved for HCC treatment targeting the VEGFR (vascular endothelial growth factor receptor) (Llovet et al, 2016; Villanueva, 2019). The PD-1 checkpoint inhibitor nivolumab was reported with conditional approval for sorafenib-treated patients in the United States (Huppert et al, 2020). Being usually diagnosed at an advanced stage, HCC patients clinically receive limited survival benefits from single-drug treatments due to the adaptive therapeutic resistance rapidly developed (Tagliamonte et al, 2020). While conventional chemotherapy was frequently hesitated to recommend, the 5-year survival rate of HCC was reported to be only 18% (Villanueva, 2019). 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
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