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Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells
The purpose of this study was to determine the potential benefits of combination therapy using dimercaptosuccinic acid modified iron oxide (DMSA-Fe(3)O(4)) magnetic nanoparticles (MNPs) combined with nontoxic concentration of bortezomib (BTZ) and gambogic acid (GA) on multiple myeloma (MM) RPMI-8226...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425315/ https://www.ncbi.nlm.nih.gov/pubmed/25995634 http://dx.doi.org/10.2147/IJN.S80795 |
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author | Zhang, Wei Qiao, Lixing Wang, Xinchao Senthilkumar, Ravichandran Wang, Fei Chen, Baoan |
author_facet | Zhang, Wei Qiao, Lixing Wang, Xinchao Senthilkumar, Ravichandran Wang, Fei Chen, Baoan |
author_sort | Zhang, Wei |
collection | PubMed |
description | The purpose of this study was to determine the potential benefits of combination therapy using dimercaptosuccinic acid modified iron oxide (DMSA-Fe(3)O(4)) magnetic nanoparticles (MNPs) combined with nontoxic concentration of bortezomib (BTZ) and gambogic acid (GA) on multiple myeloma (MM) RPMI-8226 cells and possible underlying mechanisms. The effects of BTZ-GA-loaded MNP-Fe(3)O(4) (BTZ-GA/MNPs) on cell proliferation were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,4,-diphenyltetrazolium bromide (MTT) method. Cell cycle and apoptosis were detected using the terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay and flow cytometry (FCM). Furthermore, DMSA-Fe(3)O(4) MNPs were characterized in terms of distribution, apoptotic morphology, and cellular uptake by transmission electron microscopy (TEM) and 4,6-diamidino-2-phenylindole (DAPI) staining. Subsequently, the effect of BTZ-GA/MNPs combination on PI3K/Akt activation and apoptotic-related protein were appraised by Western blotting. MTT assay and hematoxylin and eosin (HE) staining were applied to elevate the functions of BTZ-GA/MNPs combination on the tumor xenograft model and tumor necrosis. The results of this study revealed that the majority of MNPs were quasi-spherical and the MNPs taken up by cells were located in the endosome vesicles of cytoplasm. Nontoxic concentration of BTZ-GA/MNPs increased G(2)/M phase cell cycle arrest and induced apoptosis in RPMI-8226 cells. Furthermore, the combination of BTZ-GA/MNPs activated phosphorylated Akt levels, Caspase-3, and Bax expression, and down-regulated the PI3K and Bcl-2 levels significantly. Meanwhile, the in vivo tumor xenograft model indicated that the treatment of BTZ-GA/MNPs decreased the tumor growth and volume and induced cell apoptosis and necrosis. These findings suggest that chemotherapeutic agents polymerized MNPs-Fe(3)O(4) with GA could serve as a better alternative for targeted therapeutic approaches to treat multiple myeloma. |
format | Online Article Text |
id | pubmed-4425315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-44253152015-05-20 Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells Zhang, Wei Qiao, Lixing Wang, Xinchao Senthilkumar, Ravichandran Wang, Fei Chen, Baoan Int J Nanomedicine Original Research The purpose of this study was to determine the potential benefits of combination therapy using dimercaptosuccinic acid modified iron oxide (DMSA-Fe(3)O(4)) magnetic nanoparticles (MNPs) combined with nontoxic concentration of bortezomib (BTZ) and gambogic acid (GA) on multiple myeloma (MM) RPMI-8226 cells and possible underlying mechanisms. The effects of BTZ-GA-loaded MNP-Fe(3)O(4) (BTZ-GA/MNPs) on cell proliferation were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,4,-diphenyltetrazolium bromide (MTT) method. Cell cycle and apoptosis were detected using the terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay and flow cytometry (FCM). Furthermore, DMSA-Fe(3)O(4) MNPs were characterized in terms of distribution, apoptotic morphology, and cellular uptake by transmission electron microscopy (TEM) and 4,6-diamidino-2-phenylindole (DAPI) staining. Subsequently, the effect of BTZ-GA/MNPs combination on PI3K/Akt activation and apoptotic-related protein were appraised by Western blotting. MTT assay and hematoxylin and eosin (HE) staining were applied to elevate the functions of BTZ-GA/MNPs combination on the tumor xenograft model and tumor necrosis. The results of this study revealed that the majority of MNPs were quasi-spherical and the MNPs taken up by cells were located in the endosome vesicles of cytoplasm. Nontoxic concentration of BTZ-GA/MNPs increased G(2)/M phase cell cycle arrest and induced apoptosis in RPMI-8226 cells. Furthermore, the combination of BTZ-GA/MNPs activated phosphorylated Akt levels, Caspase-3, and Bax expression, and down-regulated the PI3K and Bcl-2 levels significantly. Meanwhile, the in vivo tumor xenograft model indicated that the treatment of BTZ-GA/MNPs decreased the tumor growth and volume and induced cell apoptosis and necrosis. These findings suggest that chemotherapeutic agents polymerized MNPs-Fe(3)O(4) with GA could serve as a better alternative for targeted therapeutic approaches to treat multiple myeloma. Dove Medical Press 2015-04-30 /pmc/articles/PMC4425315/ /pubmed/25995634 http://dx.doi.org/10.2147/IJN.S80795 Text en © 2015 Zhang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Zhang, Wei Qiao, Lixing Wang, Xinchao Senthilkumar, Ravichandran Wang, Fei Chen, Baoan Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells |
title | Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells |
title_full | Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells |
title_fullStr | Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells |
title_full_unstemmed | Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells |
title_short | Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe(3)O(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells |
title_sort | inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified fe(3)o(4) magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in rpmi-8226 cells |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425315/ https://www.ncbi.nlm.nih.gov/pubmed/25995634 http://dx.doi.org/10.2147/IJN.S80795 |
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