Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe3O4 magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells
Wei Zhang,1* Lixing Qiao,2* Xinchao Wang,3* Ravichandran Senthilkumar,1 Fei Wang,1 Baoan Chen1,4 1Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Pediatrics, Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Repub...
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| Autores principales: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2015
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/db6caba790c14dd4b4511c91513a6a61 |
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| Sumario: | Wei Zhang,1* Lixing Qiao,2* Xinchao Wang,3* Ravichandran Senthilkumar,1 Fei Wang,1 Baoan Chen1,4 1Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Pediatrics, Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Republic of China; 3Department of Thyroid and Breast, the Fourth Central Hospital, Tianjin, People’s Republic of China; 4Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: The purpose of this study was to determine the potential benefits of combination therapy using dimercaptosuccinic acid modified iron oxide (DMSA-Fe3O4) 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-Fe3O4 (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-Fe3O4 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 G2/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-Fe3O4 with GA could serve as a better alternative for targeted therapeutic approaches to treat multiple myeloma. Keywords: magnetic nanoparticles, DMSA-Fe3O4, bortezomib, gambogic acid, PI3K/Akt, cell cycle, apoptosis |
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