Cargando…
Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable phar...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793079/ https://www.ncbi.nlm.nih.gov/pubmed/31631978 http://dx.doi.org/10.2147/DDDT.S216542 |
_version_ | 1783459177765535744 |
---|---|
author | Xu, Xiaohong Rajamanickam, Vinothkumar Shu, Sheng Liu, Zhoudi Yan, Tao He, Jinxin Liu, Zhiguo Guo, Guilong Liang, Guang Wang, Yi |
author_facet | Xu, Xiaohong Rajamanickam, Vinothkumar Shu, Sheng Liu, Zhoudi Yan, Tao He, Jinxin Liu, Zhiguo Guo, Guilong Liang, Guang Wang, Yi |
author_sort | Xu, Xiaohong |
collection | PubMed |
description | BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. METHODS: Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. RESULTS: Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. CONCLUSION: Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway. |
format | Online Article Text |
id | pubmed-6793079 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-67930792019-10-18 Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway Xu, Xiaohong Rajamanickam, Vinothkumar Shu, Sheng Liu, Zhoudi Yan, Tao He, Jinxin Liu, Zhiguo Guo, Guilong Liang, Guang Wang, Yi Drug Des Devel Ther Original Research BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. METHODS: Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. RESULTS: Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. CONCLUSION: Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway. Dove 2019-10-11 /pmc/articles/PMC6793079/ /pubmed/31631978 http://dx.doi.org/10.2147/DDDT.S216542 Text en © 2019 Xu et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Xu, Xiaohong Rajamanickam, Vinothkumar Shu, Sheng Liu, Zhoudi Yan, Tao He, Jinxin Liu, Zhiguo Guo, Guilong Liang, Guang Wang, Yi Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway |
title | Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway |
title_full | Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway |
title_fullStr | Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway |
title_full_unstemmed | Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway |
title_short | Indole-2-Carboxamide Derivative LG25 Inhibits Triple-Negative Breast Cancer Growth By Suppressing Akt/mTOR/NF-κB Signalling Pathway |
title_sort | indole-2-carboxamide derivative lg25 inhibits triple-negative breast cancer growth by suppressing akt/mtor/nf-κb signalling pathway |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793079/ https://www.ncbi.nlm.nih.gov/pubmed/31631978 http://dx.doi.org/10.2147/DDDT.S216542 |
work_keys_str_mv | AT xuxiaohong indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT rajamanickamvinothkumar indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT shusheng indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT liuzhoudi indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT yantao indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT hejinxin indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT liuzhiguo indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT guoguilong indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT liangguang indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway AT wangyi indole2carboxamidederivativelg25inhibitstriplenegativebreastcancergrowthbysuppressingaktmtornfkbsignallingpathway |