Copyright
©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2022; 14(2): 450-477
Published online Feb 15, 2022. doi: 10.4251/wjgo.v14.i2.450
Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways
Piao Zheng, Zhen Huang, Dong-Chang Tong, Qing Zhou, Sha Tian, Bo-Wei Chen, Di-Min Ning, Yin-Mei Guo, Wen-Hao Zhu, Yan Long, Wei Xiao, Zhe Deng, Yi-Chen Lei, Xue-Fei Tian
Piao Zheng, Zhen Huang, Dong-Chang Tong, Sha Tian, Di-Min Ning, Wen-Hao Zhu, Zhe Deng, Yi-Chen Lei, Xue-Fei Tian, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Piao Zheng, Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
Qing Zhou, Bo-Wei Chen, Yan Long, The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha 410021, Hunan Province, China
Yin-Mei Guo, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Wei Xiao, Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
Author contributions: Tian XF provided the conceptual and technical guidance, designed the study, and revised the manuscript critically for important intellectual content; Zheng P, Tian S and Zhou Q coordinated the study; Zheng P, Huang Z, Tong DC, Ning DM, Guo YM, Zhu WH, Long Y, Deng Z and Lei YC performed the experiments; Zheng P, Chen BW and Xiao W interpreted data; Zheng P wrote the manuscript; all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. U20A20408 (Major Program) and No. 82074450 (General Program); Natural Science Foundation of Hunan Province, No. 2020JJ4066; Hunan Province Research and innovation projects for Postgraduates, No. CX20190541; Hunan Province "domestic first-class cultivation discipline" Integrated Traditional Chinese and Western medicine open fund project, No. 2018ZXYJH03; Hunan University Undergraduate Research Learning and Innovative Experiment Project, No. 201609030114.
Institutional animal care and use committee statement: This research was reviewed and approved by the Committee on the Ethics of Animal Experiments of Hunan University of Chinese Medicine, No. LL2020102801. All animal experiments were conducted in accordance with international standards and under the guidelines for animal care and use formulated by the Animal Experiment Center of Hunan University of Chinese Medicine.
Conflict-of-interest statement: All authors declare no financial or commercial conflict of interest.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Xue-Fei Tian, PhD, Professor, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, No. 300 Xueshi Road, Yuelu District, Changsha 410208, Hunan Province, China. 003640@hnucm.edu.cn
Received: July 22, 2021
Peer-review started: July 22, 2021
First decision: November 8, 2021
Revised: November 19, 2021
Accepted: January 14, 2022
Article in press: January 14, 2022
Published online: February 15, 2022
Processing time: 202 Days and 23.7 Hours
ARTICLE HIGHLIGHTS
Research background
Hepatocellular carcinoma (HCC) has the characteristics of high morbidity, high recurrence rate, high metastasis rate and high mortality rate, which seriously threaten human health. Therefore, it is necessary to find new treatment methods. In traditional Chinese medicine (TCM), the anti-HCC activity of the antitumor drug Xihuang Pill has attracted attention.
Research conclusions
Frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways.
Research results
There are 35 active ingredients in frankincense and myrrh, with 151 key targets, and they may play roles in the treatment of HCC by regulating the hypoxia response and vascular-system-related pathological processes. Compared with the control group, after treatment with frankincense and/or myrrh, the volume of transplanted subcutaneously HCC tumors was significantly reduced, and the pathological morphology was weakened. The expression levels of CD31 and collagen IV were downregulated; the coverage of cells around blood vessels was upregulated; the connections between cells were tightened, and the shape of blood vessels was improved. In addition, frankincense and/or myrrh treatment downregulated the expression levels of HIF-1α, TNF-α, VEGF and MMP-9 and downregulated the phosphorylation activity of EGFR and downstream target PI3K/Akt and MAPK (ERK, p38 and JNK) pathway-related proteins.
Research methods
Bioinformatics analysis was used to predict the efficacy and possible mechanism of frankincense and myrrh in HCC and to screen core predictive targets. BALB/c nude mice were introduced in vivo to establish an HCC subcutaneous tumor model. The tumor volume and growth rate were evaluated, and histopathological examination was used to detect tumor growth, proliferation and pathological changes. Immunofluorescence and transmission electron microscopy were used to observe the expression of CD31, α-SMA and collagen IV and the morphology of vascular endothelial cells and pericytes. Enzyme-linked immunosorbent assay was utilized to detect the secretion of HIF-1α and TNF-α. Reverse transcription-quantitative polymerase chain reaction was applied to detect the expression levels of HIF-1α, TNF-α, VEGF and MMP-9. Western blot was adopted to detect EGFR and its mediated PI3K/Akt, MAPK (ERK, p38 and JNK) core signaling pathways and other key proteins as well as HIF-1α and TNF-α protein expression.
Research objectives
To study the potential anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.
Research motivation
The main components of Xihuang Pill, frankincense and myrrh, have shown anticancer activities in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of HCC is unclear, and the underlying molecular mechanism has not yet been determined.
Research perspectives
The dual TCM compound frankincense and myrrh has the potential to become an anti-HCC drug candidate.
