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

• Published in: International journal of nanomedicine Vol. 10; pp. 3275 - 3289
• Main Authors: Chen, Baoan, Wang, Fei, Zhang, Wei, Wang, Xinchao, Senthilkumar, Ravichandran, Qiao, Lixing
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01.01.2015; Dove Press; Dove Medical Press
• Subjects: ABC transporters; Acids; Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; Biomedical materials; bortezomib; Bortezomib - chemistry; Bortezomib - toxicity; Cancer therapies; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cytotoxicity; DMSA-Fe3O4; Drug delivery systems; Drug dosages; gambogic acid; Hematology; Humans; Hypoxia; Inhibitor drugs; Kinases; Laboratories; Leukemia; magnetic nanoparticles; Magnetite Nanoparticles - chemistry; Magnetite Nanoparticles - toxicity; Medical research; Multiple myeloma; Nanoparticles; NMR; Nuclear magnetic resonance; Original Research; Pharmaceuticals; PI3K/Akt; Proteins; Succimer - chemistry; Targeted cancer therapy; Xanthones - chemistry; Xanthones - pharmacology; United States > US; China; DMSA-Fe3O4; gambogic acid; cell cycle; apoptosis; bortezomib; magnetic nanoparticles; PI3K/Akt
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S80795

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.