1. Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer
- Author
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Xiao, Kai, Li, Yuan-Pei, Wang, Cheng, Ahmad, Sarah, Vu, Michael, Kuma, Krishneel, Cheng, Yi-Qiang, and Lam, Kit S
- Subjects
Nude ,Biomedical Engineering ,Breast Neoplasms ,Apoptosis ,Cell Line ,Thailandepsin A ,Histones ,Bortezomib ,Mice ,Breast cancer ,HDAC inhibitor ,Depsipeptides ,Animals ,Humans ,Tissue Distribution ,Disulfides ,Particle Size ,Micelles ,Disulfide cross-linked micelle ,Cell Proliferation ,Cancer ,Tumor ,Cell Cycle ,Acetylation ,Xenograft Model Antitumor Assays ,Endocytosis ,Mitochondria ,Histone Deacetylase Inhibitors ,Cross-Linking Reagents ,5.1 Pharmaceuticals ,Female ,Targeted delivery ,Development of treatments and therapeutic interventions ,Reactive Oxygen Species - 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±4nm), 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.
- Published
- 2015