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      Anti-Hepatoma Compound Determination by the Method of Spectrum Effect Relationship, Component Knock-Out, and UPLC-MS 2 in Scheflera heptaphylla (L.)Frodin Harms and Its Mechanism

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          Abstract

          Scheflera heptaphylla (L.)Frodin, a kind of Traditional Chinese Medicine, is commonly used in anti-inflammatory, analgesic, anti-viral, anti-tumor, and hemostasis. This study aimed to determine the anti-hepatoma components and its mechanism from the leaves of S. heptaphylla. The spectrum-effect relationships were analyzed by the method of Partial least squares, indicating that P1, P2, and P10 were positively correlated to inhibitory activity of Huh7 cells. Whereas others were negatively correlated. The technologies of component knock-out and UPLC-MS 2 were used to determine compounds as 3,4-Dicaffeoylquinic acid (P6), 3,5-Dicaffeoylquinic acid (P7), 3 α-Hydroxy-lup-20(29)-ene-23,28-dioic acid (P10, named Compound A). The results forecasted that Compound A had the best correlation with inhibitory activity. The effects of Compound A on the activities of human hepatoma cells (Huh7, SMMC-7721, HepG 2) and normal hepatocytes (L0-2, Chang liver) were evaluated. Cell apoptosis was observed with inverted microscope and flow cytometer. In addition, the proteins, related to apoptosis, were detected by Western blot. The results showed that Compound A (400 nM) could significantly inhibit the activity of three hepatoma cells ( P < 0.001) with slight toxicity to normal hepatocytes, and the IC 50 values were 285.3 and 315.1 nM, respectively, which were consistent with the prediction of spectrum-effect relationships. After treatment with Compound A, the number of hepatoma cells decreased significantly. And the apoptosis rate of Huh7 cells increased significantly ( P < 0.001) in Compound A (200, 400 nM) groups, SMMC-7721 and HepG 2 were directly necrotic. Compound A groups could significantly improve the level of intracellular reactive oxygen species (ROS) ( P < 0.05, P < 0.001) in Huh7 with no effect on normal hepatocytes. The content of apoptotic protein (Bax and Bim) in mitochondria was significantly increased in Compound A groups ( P < 0.001). On the contrary, the content of anti-apoptotic protein (Bcl-xL and Mcl-1) decreased significantly ( P < 0.001). These results demonstrated that Compound A was the main anti-hepatoma active component in the S. heptaphylla leaves. It achieved the effect of promoting apoptosis of Huh7 cells by regulating the levels of ROS and Bcl-2 family protein in mitochondrial apoptosis pathway.

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          Most cited references 32

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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                09 September 2020
                2020
                : 11
                Affiliations
                [1] 1National R & D Center for Edible Fungus Processing Technology, Henan University , Kaifeng, China
                [2] 2School of Biomedical Sciences, Huaqiao University , Xiamen, China
                [3] 3Joint International Research Laboratory of Food & Medicine Resource Function, Henan Province, Henan University , Kaifeng, China
                [4] 4Hebei Food Inspection and Research Institute , Shijiazhuang, China
                [5] 5College of Forensic Medicine, Hebei Medical University , Shijiazhuang, China
                Author notes

                Edited by: Yi Wang, Zhejiang University, China

                Reviewed by: Liang Feng, China Pharmaceutical University, China; Fatma Mohamady El-Demerdash, Alexandria University, Egypt

                *Correspondence: Zhenhua Liu, liuzhenhua623@ 123456163.com ; Yan Zhang, snowwinglv@ 123456126.com ; Wenyi Kang, kangweny@ 123456hotmail.com

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.01342
                7509203
                14c5e248-43cc-4b7b-b9a2-add28848f6e2
                Copyright © 2020 Liu, Jiang, Xu, Liu, Liu, Zhang and Kang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 10, Tables: 4, Equations: 2, References: 41, Pages: 13, Words: 6662
                Categories
                Pharmacology
                Original Research

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