A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-κB Activation

Yanqiong Zhang; Xia Mao; Wenjia Chen; Xiaodong Guo; Liangxiang Yu; Funeng Jiang; Xiaoyue Wang; Weijie Li; Qiuyan Guo; Taixian Li; Na Lin

doi:10.1016/j.omtn.2019.12.023

A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-κB Activation

Mol Ther Nucleic Acids. 2020 Mar 6:19:890-904. doi: 10.1016/j.omtn.2019.12.023. Epub 2020 Jan 10.

Authors

Yanqiong Zhang¹, Xia Mao², Wenjia Chen², Xiaodong Guo³, Liangxiang Yu³, Funeng Jiang⁴, Xiaoyue Wang², Weijie Li², Qiuyan Guo², Taixian Li², Na Lin⁵

Affiliations

¹ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: yqzhang@icmm.ac.cn.
² Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
³ 302 Military Hospital, Beijing 100039, China.
⁴ The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510230, China.
⁵ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: nlin@icmm.ac.cn.

Abstract

Drug repositioning offers new clinical applications for existing drugs with shorter approval processes and lower costs and risks than de novo experimental drug development. The Fufang-Biejia-Ruangan pill (FBRP) is the first clinically approved anti-fibrosis herbal formula in China. Whether FBRP could be used to treat hepatocellular carcinoma (HCC) remains unclear. Herein, a total of 161 FBRP candidate targets against HCC were identified according to the topological importance in the "hepatic fibrosis-cirrhosis-cancer axis-related gene-FBRP putative target" network, and mostly enriched in phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear factor κB (NF-κB) signaling. Experimentally, FBRP inhibited liver fibrosis and prevented the development of neoplastic lesions at the early stages of hepatocarcinogenesis in a diethylnitrosamine-induced rat HCC model. FBRP inhibited tumor cell proliferation, induced tumor-specific cell death, and suppressed tumor progression in HCC rats while preventing the activation of PI3K, AKT and IKΚB proteins, reducing the nuclear accumulation of NFΚB1 protein, and decreasing the downstream expression of proteins. Consistently, FBRP suppressed HCC cell proliferation and induced cell cycle arrest in vitro. Co-treatment of FBRP with PI3K inhibitor exhibited an additive inhibitory effect on PI3K/AKT/NF-κB activation. Collectively, our data showed the potentials of FBRP in hepatic fibrosis microenvironment regulation and tumor prevention, suggesting that FBRP may be a promising candidate drug for reduction of fibrogenesis and prevention of HCC.

Keywords: Fufang-Biejia-Ruangan pill; PI3K/AKT/NF-κB signaling; biological molecular network; hepatic fibrosis; hepatocellular carcinoma.