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Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway
PURPOSE: The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the mechanism of this combined therapy, which may provide innovative strategies for treating this disease. METHODS: The viability of...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517494/ https://www.ncbi.nlm.nih.gov/pubmed/37740231 http://dx.doi.org/10.1186/s40360-023-00686-7 |
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author | Sheng, Bo Wang, Wenwen Xia, Dongyue Qu, Xiangdong |
author_facet | Sheng, Bo Wang, Wenwen Xia, Dongyue Qu, Xiangdong |
author_sort | Sheng, Bo |
collection | PubMed |
description | PURPOSE: The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the mechanism of this combined therapy, which may provide innovative strategies for treating this disease. METHODS: The viability of the cervical cancer cells was measured by cell counting kit-8 (CCK-8) assay, and the synergistic effect was analyzed using SynergyFinder. Cell proliferation was tested by cell cloning. The apoptosis and reactive oxygen species (ROS) production in cervical cancer cells were analyzed by flow cytometry. Western blot and quantitative real-time PCR (qRT-PCR) were employed to determine changes in protein and gene levels of pathway-related factors. RESULTS: By the results of cytotoxicity assay, SiHa cells were selected and treated with 0.1 μM LBH589 and 4 μM AM1241 for 24 h for subsequent experiments. The combination of both was synergistic as determined by bliss, ZIP, HSA and LOEWE synergy score. Plate cloning results showed that LBH589 combined with AM1241 inhibited the proliferation of cervical cancer cells compared to individual drug. Additionally, compared with LBH589 alone, the combination of LBH589 and AM1241 induced autophagy by increasing LC3II/LC3I and decreasing P62/GAPDH, leading to a significantly higher rate of apoptosis. Pharmacological inhibition of also inhibited apoptosis. Consistently, we found that the endoplasmic reticulum, DNA damage repair pathway were induced after co-administration. Furthermore, cellular ROS increased after co-administration, and apoptosis was inhibited by the addition of ROS scavenger. CONCLUSION: LBH589 combined with AM1241 activated the endoplasmic reticulum emergency pathway, DNA damage repair signaling pathway, oxidative stress and autophagy pathway, ultimately promoting the apoptosis of cervical cancer cells. These findings suggest that the co-administration of LBH589 and AM1241 may be a new treatment plan for the treatment of cervical cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40360-023-00686-7. |
format | Online Article Text |
id | pubmed-10517494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-105174942023-09-24 Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway Sheng, Bo Wang, Wenwen Xia, Dongyue Qu, Xiangdong BMC Pharmacol Toxicol Research PURPOSE: The study aims to investigate the apoptotic effects of combining LBH589 and AM1241 (a selective CB2 receptor agonist) on cervical cancer cells and elucidating the mechanism of this combined therapy, which may provide innovative strategies for treating this disease. METHODS: The viability of the cervical cancer cells was measured by cell counting kit-8 (CCK-8) assay, and the synergistic effect was analyzed using SynergyFinder. Cell proliferation was tested by cell cloning. The apoptosis and reactive oxygen species (ROS) production in cervical cancer cells were analyzed by flow cytometry. Western blot and quantitative real-time PCR (qRT-PCR) were employed to determine changes in protein and gene levels of pathway-related factors. RESULTS: By the results of cytotoxicity assay, SiHa cells were selected and treated with 0.1 μM LBH589 and 4 μM AM1241 for 24 h for subsequent experiments. The combination of both was synergistic as determined by bliss, ZIP, HSA and LOEWE synergy score. Plate cloning results showed that LBH589 combined with AM1241 inhibited the proliferation of cervical cancer cells compared to individual drug. Additionally, compared with LBH589 alone, the combination of LBH589 and AM1241 induced autophagy by increasing LC3II/LC3I and decreasing P62/GAPDH, leading to a significantly higher rate of apoptosis. Pharmacological inhibition of also inhibited apoptosis. Consistently, we found that the endoplasmic reticulum, DNA damage repair pathway were induced after co-administration. Furthermore, cellular ROS increased after co-administration, and apoptosis was inhibited by the addition of ROS scavenger. CONCLUSION: LBH589 combined with AM1241 activated the endoplasmic reticulum emergency pathway, DNA damage repair signaling pathway, oxidative stress and autophagy pathway, ultimately promoting the apoptosis of cervical cancer cells. These findings suggest that the co-administration of LBH589 and AM1241 may be a new treatment plan for the treatment of cervical cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40360-023-00686-7. BioMed Central 2023-09-22 /pmc/articles/PMC10517494/ /pubmed/37740231 http://dx.doi.org/10.1186/s40360-023-00686-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Sheng, Bo Wang, Wenwen Xia, Dongyue Qu, Xiangdong Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway |
title | Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway |
title_full | Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway |
title_fullStr | Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway |
title_full_unstemmed | Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway |
title_short | Panobinostat (LBH589) combined with AM1241 induces cervical cancer cell apoptosis through autophagy pathway |
title_sort | panobinostat (lbh589) combined with am1241 induces cervical cancer cell apoptosis through autophagy pathway |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517494/ https://www.ncbi.nlm.nih.gov/pubmed/37740231 http://dx.doi.org/10.1186/s40360-023-00686-7 |
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