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Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells
Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560791/ https://www.ncbi.nlm.nih.gov/pubmed/34737698 http://dx.doi.org/10.3389/fphar.2021.714628 |
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author | Zhang, Yu-Zhu Yang, Jia-Yao Wu, Rui-Xian Fang, Chen Lu, Hai Li, Hua-Chao Li, Dong-Mei Zuo, Hua-Li Ren, Li-Ping Liu, Xiao-Yuan Xu, Rui Wen, Jia-Huai Huang, Hsien-Da Hong, Ri Chen, Qian-Jun |
author_facet | Zhang, Yu-Zhu Yang, Jia-Yao Wu, Rui-Xian Fang, Chen Lu, Hai Li, Hua-Chao Li, Dong-Mei Zuo, Hua-Li Ren, Li-Ping Liu, Xiao-Yuan Xu, Rui Wen, Jia-Huai Huang, Hsien-Da Hong, Ri Chen, Qian-Jun |
author_sort | Zhang, Yu-Zhu |
collection | PubMed |
description | Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell–related genes were identified. The drug–herb–active compound–target gene–disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene. |
format | Online Article Text |
id | pubmed-8560791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85607912021-11-03 Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells Zhang, Yu-Zhu Yang, Jia-Yao Wu, Rui-Xian Fang, Chen Lu, Hai Li, Hua-Chao Li, Dong-Mei Zuo, Hua-Li Ren, Li-Ping Liu, Xiao-Yuan Xu, Rui Wen, Jia-Huai Huang, Hsien-Da Hong, Ri Chen, Qian-Jun Front Pharmacol Pharmacology Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell–related genes were identified. The drug–herb–active compound–target gene–disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene. Frontiers Media S.A. 2021-10-19 /pmc/articles/PMC8560791/ /pubmed/34737698 http://dx.doi.org/10.3389/fphar.2021.714628 Text en Copyright © 2021 Zhang, Yang, Wu, Fang, Lu, Li, Li, Zuo, Ren, Liu, Xu, Wen, Huang, Hong and Chen. https://creativecommons.org/licenses/by/4.0/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. |
spellingShingle | Pharmacology Zhang, Yu-Zhu Yang, Jia-Yao Wu, Rui-Xian Fang, Chen Lu, Hai Li, Hua-Chao Li, Dong-Mei Zuo, Hua-Li Ren, Li-Ping Liu, Xiao-Yuan Xu, Rui Wen, Jia-Huai Huang, Hsien-Da Hong, Ri Chen, Qian-Jun Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells |
title | Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells |
title_full | Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells |
title_fullStr | Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells |
title_full_unstemmed | Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells |
title_short | Network Pharmacology–Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells |
title_sort | network pharmacology–based identification of key mechanisms of xihuang pill in the treatment of triple-negative breast cancer stem cells |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560791/ https://www.ncbi.nlm.nih.gov/pubmed/34737698 http://dx.doi.org/10.3389/fphar.2021.714628 |
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