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Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer.
- Source :
-
Biomaterials [Biomaterials] 2015 Oct; Vol. 67, pp. 183-93. Date of Electronic Publication: 2015 Jul 17. - Publication Year :
- 2015
-
Abstract
- Histone deacetylase (HDAC) inhibitors are an emerging class of targeted therapy against cancers. Thailandepsin A (TDP-A) is a recently discovered class I HDAC inhibitor with broad anti-proliferative activities. In the present study, we aimed to investigate the potential of TDP-A in the treatment of breast cancer. We demonstrated that TDP-A inhibited cell proliferation and induced apoptosis in breast cancer cells at low nanomolar concentrations. TDP-A activated the intrinsic apoptotic pathway through increase of pro-apoptotic protein Bax, decrease of anti-apoptotic Bcl-2, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). TDP-A also induced cell cycle arrest at the G2/M phase, and promoted the production of reactive oxygen species (ROS). We have successfully encapsulated TDP-A into our recently developed disulfide cross-linked micelles (DCMs), improving its water solubility and targeted delivery. TDP-A loaded DCMs (TDP-A/DCMs) possess the characteristics of high loading capacity (>20%, w/w), optimal and monodisperse particle size (16 ± 4 nm), outstanding stability with redox stimuli-responsive disintegration, sustained drug release, and preferential uptake in breast tumors. In the MDA-MB-231 breast cancer xenograft model, TDP-A/DCMs were more efficacious than the FDA-approved FK228 at well-tolerated doses. Furthermore, TDP-A/DCMs exhibited synergistic anticancer effects when combined with the proteasome inhibitor bortezomib (BTZ) loaded DCMs (BTZ/DCMs). Our results indicate that TDP-A nanoformulation alone or in combination with BTZ nanoformulation are efficacious against breast cancer.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetylation drug effects
Animals
Apoptosis drug effects
Bortezomib pharmacology
Breast Neoplasms pathology
Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Depsipeptides chemistry
Depsipeptides pharmacology
Endocytosis drug effects
Female
Histone Deacetylase Inhibitors chemistry
Histone Deacetylase Inhibitors pharmacology
Histones metabolism
Humans
Mice, Nude
Mitochondria drug effects
Mitochondria metabolism
Particle Size
Reactive Oxygen Species metabolism
Tissue Distribution drug effects
Xenograft Model Antitumor Assays
Breast Neoplasms drug therapy
Cross-Linking Reagents chemistry
Depsipeptides therapeutic use
Disulfides chemistry
Histone Deacetylase Inhibitors therapeutic use
Micelles
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5905
- Volume :
- 67
- Database :
- MEDLINE
- Journal :
- Biomaterials
- Publication Type :
- Academic Journal
- Accession number :
- 26218744
- Full Text :
- https://doi.org/10.1016/j.biomaterials.2015.07.033