Cargando…
Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway
Colorectal carcinoma (CRC) is a kind of malignant tumor closely related to ulcerative colitis. Xanthone derivatives are one of the most promising therapeutic drugs which have been used in phase I/II clinical trials for cancer therapy. Our previous study indicated that the aerial parts of Gentianella...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917368/ https://www.ncbi.nlm.nih.gov/pubmed/36768602 http://dx.doi.org/10.3390/ijms24032279 |
_version_ | 1784886349118046208 |
---|---|
author | Lu, Meng-Qi Ruan, Jing-Ya Li, Hui-Min Yang, Ding-Shan Liu, Yan-Xia Hao, Mi-Mi Yu, Hai-Yang Zhang, Yi Wang, Tao |
author_facet | Lu, Meng-Qi Ruan, Jing-Ya Li, Hui-Min Yang, Ding-Shan Liu, Yan-Xia Hao, Mi-Mi Yu, Hai-Yang Zhang, Yi Wang, Tao |
author_sort | Lu, Meng-Qi |
collection | PubMed |
description | Colorectal carcinoma (CRC) is a kind of malignant tumor closely related to ulcerative colitis. Xanthone derivatives are one of the most promising therapeutic drugs which have been used in phase I/II clinical trials for cancer therapy. Our previous study indicated that the aerial parts of Gentianella acuta Michx. Hulten (GA) was rich in xanthones and showed a good therapeutic effect on ulcerative colitis in mice, suggesting that GA xanthones might have some therapeutic or ameliorative effects on CRC. However, no relevant study has been reported. This study aims to find the effective substances of GA inhibiting CRC and clarify their mechanism. Solvent extraction, column chromatographic separation, and LC-MS analysis were used to characterize the 70% EtOH extract of GA and track xanthones abundant fraction XF. MTT assay was carried out to clarify the activity of GA fractions; the result showed XF to be the main active fraction. LC-MS analysis was executed to characterize XF, 38 xanthones were identified. Network pharmacology prediction, in vitro activity screening, and molecular docking assay were combined to predict the potential mechanism; the PI3K/Akt/mTOR signaling pathway was found to be most important. Western blot assay on the main active xanthones 1,3,5-trihydroxyxanthone (16), 1,3,5,8-tetrahydroxyxanthone (17), 1,5,8-trihydroxy-3-methoxyxanthone (18), and 1,7-dihydroxy-3,8-dimethoxyxanthone (19) was used to verify the above prediction; these xanthones were found to inhibit the PI3K/Akt/mTOR signaling pathway, and 17 played a significant role among them through Western blot assay using PI3K/AKT/mTOR agonist IGF-1. In conclusion, this study demonstrated that GA xanthones were effective compounds of GA inhibiting CRC by regulating PI3K/Akt/mTOR signaling pathway transduction, at least. Importantly, 1,3,5,8-tetrahydroxyxanthone (17), the most abundant active xanthone in GA, might be a candidate drug for CRC. |
format | Online Article Text |
id | pubmed-9917368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99173682023-02-11 Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway Lu, Meng-Qi Ruan, Jing-Ya Li, Hui-Min Yang, Ding-Shan Liu, Yan-Xia Hao, Mi-Mi Yu, Hai-Yang Zhang, Yi Wang, Tao Int J Mol Sci Article Colorectal carcinoma (CRC) is a kind of malignant tumor closely related to ulcerative colitis. Xanthone derivatives are one of the most promising therapeutic drugs which have been used in phase I/II clinical trials for cancer therapy. Our previous study indicated that the aerial parts of Gentianella acuta Michx. Hulten (GA) was rich in xanthones and showed a good therapeutic effect on ulcerative colitis in mice, suggesting that GA xanthones might have some therapeutic or ameliorative effects on CRC. However, no relevant study has been reported. This study aims to find the effective substances of GA inhibiting CRC and clarify their mechanism. Solvent extraction, column chromatographic separation, and LC-MS analysis were used to characterize the 70% EtOH extract of GA and track xanthones abundant fraction XF. MTT assay was carried out to clarify the activity of GA fractions; the result showed XF to be the main active fraction. LC-MS analysis was executed to characterize XF, 38 xanthones were identified. Network pharmacology prediction, in vitro activity screening, and molecular docking assay were combined to predict the potential mechanism; the PI3K/Akt/mTOR signaling pathway was found to be most important. Western blot assay on the main active xanthones 1,3,5-trihydroxyxanthone (16), 1,3,5,8-tetrahydroxyxanthone (17), 1,5,8-trihydroxy-3-methoxyxanthone (18), and 1,7-dihydroxy-3,8-dimethoxyxanthone (19) was used to verify the above prediction; these xanthones were found to inhibit the PI3K/Akt/mTOR signaling pathway, and 17 played a significant role among them through Western blot assay using PI3K/AKT/mTOR agonist IGF-1. In conclusion, this study demonstrated that GA xanthones were effective compounds of GA inhibiting CRC by regulating PI3K/Akt/mTOR signaling pathway transduction, at least. Importantly, 1,3,5,8-tetrahydroxyxanthone (17), the most abundant active xanthone in GA, might be a candidate drug for CRC. MDPI 2023-01-23 /pmc/articles/PMC9917368/ /pubmed/36768602 http://dx.doi.org/10.3390/ijms24032279 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lu, Meng-Qi Ruan, Jing-Ya Li, Hui-Min Yang, Ding-Shan Liu, Yan-Xia Hao, Mi-Mi Yu, Hai-Yang Zhang, Yi Wang, Tao Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway |
title | Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway |
title_full | Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway |
title_fullStr | Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway |
title_full_unstemmed | Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway |
title_short | Xanthones from Gentianella acuta (Michx.) Hulten Ameliorate Colorectal Carcinoma via the PI3K/Akt/mTOR Signaling Pathway |
title_sort | xanthones from gentianella acuta (michx.) hulten ameliorate colorectal carcinoma via the pi3k/akt/mtor signaling pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917368/ https://www.ncbi.nlm.nih.gov/pubmed/36768602 http://dx.doi.org/10.3390/ijms24032279 |
work_keys_str_mv | AT lumengqi xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT ruanjingya xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT lihuimin xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT yangdingshan xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT liuyanxia xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT haomimi xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT yuhaiyang xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT zhangyi xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway AT wangtao xanthonesfromgentianellaacutamichxhultenamelioratecolorectalcarcinomaviathepi3kaktmtorsignalingpathway |