title: Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of 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.
authors.affiliation: National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China; Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA. Electronic address: iamxiaokai@hotmail.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: Yuan-Pei
authors.initials: YP
authors.lastname: Li
authors.affiliation: UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Vu
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
authors.forename: Krishneel
authors.initials: K
authors.lastname: Kuma
authors.affiliation: UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
authors.forename: Yi-Qiang
authors.initials: YQ
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA 95817, USA. Electronic address: kslam@ucdavis.edu.
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry*; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004220:Disulfides / Q000737:chemistry*; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D008823:Micelles; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D003432:Cross-Linking Reagents; D047630:Depsipeptides; D004220:Disulfides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008823:Micelles; D017382:Reactive Oxygen Species; C574693:thailandepsin A; D000069286:Bortezomib
keywords: Breast cancer; Disulfide cross-linked micelle; HDAC inhibitor; Targeted delivery; Thailandepsin A