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

Abstract

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.

Gallium-68 Labeled Iron Oxide Nanoparticles Coated with 2,3-Dicarboxypropane-1,1-diphosphonic Acid as a Potential PET/MR Imaging Agent: A Proof-of-Concept Study

“…The later effects are probably caused by the ions released (ROS generation) by magnetic MNPs that lead to the ignition of oxidative stress responses into the cell and at the end to cytotoxicity. Moreover, although iron MNPs degraded in the cell, they can change the cellular iron pool, leading to aberrant expression of transferrin receptor, cyclins, and induction of apoptotic responses [ 35 – 37 ]. Regarding cytotoxicity, the choice of the cell line tested under MNPs treatment is of great importance, since it is demonstrated that MNPs toxicity is highly cell-type dependent [ 38 , 39 ].…”

Nanoparticles for hematologic diseases detection and treatment

“…Iron oxide NPs can enter B-cell lymphoma and multiple myeloma cells through phagocytosis and electrostatic interaction inducing cells autophagy and death. This induction of cells autophagy can be further non-invasively tuned by an external magnetic field [ 64 ] or by the addition of a chemotherapeutic agent, like bortezomib with gambogic acid [ 65 ].…”

New Opportunities for Fullerenes and for Graphene

“…A major advantage of a coating of polycyclophenazene is that it would help to reduce the tendency of the magnetic nanoparticles to aggregate together. The potential of such nanoparticles is an active area of research (Zhang et al, 2015;Kamble and Kolckar, 2014). …”