Phellodendronoside A Exerts Anticancer Effects Depending on Inducing Apoptosis Through ROS/Nrf2/Notch Pathway and Modulating Metabolite Profiles in Hepatocellular Carcinoma

Abstract

Yanpo Si,1,2 Chengcheng Hui,1 Tao Guo,1,2 Mengqi Liu,1 Xiaohui Chen,3 Chunhong Dong,3,4 Shuying Feng5 1Department of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 2Henan Engineering Research Center of Medicinal and Edible Chinese Medicine, Zhengzhou, People’s Republic of China; 3Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 4Henan Key Laboratory of Chinese Medicine for Polysaccharides and Drugs Research, Zhengzhou, People’s Republic of China; 5Medical College, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of ChinaCorrespondence: Tao Guo; Shuying Feng, Henan University of Chinese Medicine, No. 156 JinshuiEast Road, Zhengzhou, 450046, People’s Republic of China, Tel [phone], Email [email protected]; [email protected]: To reveal the potential mechanism of PDA on hepatocellular carcinoma SMMC-7721 cells in vitro.Methods: The cytotoxic activity, colony formation, cell cycle distribution, apoptosis and their associated protein analysis, intracellular reactive oxygen species (ROS) and Ca2+ levels, proteins in Nrf2 and Ntoch pathways and metabolite profiles of PDA against hepatocellular carcinoma were investigated.Results: PDA with cytotoxic activity inhibited cell proliferation and migration, increased intracellular ROS, Ca2+ levels and MCUR1 protein expression in a dose-dependent manner, caused cell cycle arrest in the S phase and induced apoptosis via adjusting the levels of Bcl-2, Bax, and Caspase 3 proteins, and inhibited the activation of Notch1, Jagged, Hes1, Nrf2 and HO-1 proteins. Metabonomics data showed that PDA significantly regulated 144 metabolite levels tend to be normal level, especially carnitine derivatives, bile acid metabolites associated with hepatocellular carcinoma, and mainly enriched in ABC transporter, arginine and proline metabolism, primary bile acid biosynthesis, Notch signaling pathway, etc, and proved that PDA markedly adjusted Notch signaling pathway.Conclusion: PDA exhibited the proliferation inhibition of SMMC-7721 cells by inhibiting ROS/Nrf2/Notch signaling pathway and significantly affected the metabolic profile, suggesting PDA could be a potential therapeutic agent for patients with hepatocellular carcinoma.Keywords: isoquinoline alkaloid, apoptosis, acylcarnitine, bile acids, metabolomics

Keywords

• isoquinoline alkaloid
• apoptosis
• acylcarnitine
• bile acids
• metabolomics