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
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Medical Biotechnology ,Oncology and Carcinogenesis ,Cancer ,Breast Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Acetylation ,Animals ,Apoptosis ,Bortezomib ,Breast Neoplasms ,Cell Cycle ,Cell Line ,Tumor ,Cell Proliferation ,Cross-Linking Reagents ,Depsipeptides ,Disulfides ,Endocytosis ,Female ,Histone Deacetylase Inhibitors ,Histones ,Humans ,Mice ,Nude ,Micelles ,Mitochondria ,Particle Size ,Reactive Oxygen Species ,Tissue Distribution ,Xenograft Model Antitumor Assays ,HDAC inhibitor ,Thailandepsin A ,Disulfide cross-linked micelle ,Targeted delivery ,Breast cancer - 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.
- Published
- 2015