Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer

Kai Xiao, Yuan Pei Li, Cheng Wang, Sarah Ahmad, Michael Vu, Krishneel Kuma, Yi Qiang Cheng, Kit S. Lam

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)183-193
Number of pages11
JournalBiomaterials
Volume67
DOIs
StatePublished - 1 Oct 2015

Fingerprint

Histone Deacetylase Inhibitors
Micelles
Disulfides
Breast Neoplasms
Cells
Administrative data processing
Disintegration
Cell proliferation
Cell death
Tumors
Solubility
Particle size
thailandepsin A
Histone Deacetylases
Proteins
Apoptosis Regulatory Proteins
Proteasome Inhibitors
Oxygen
Poly(ADP-ribose) Polymerases
G2 Phase

Keywords

  • Breast cancer
  • Disulfide cross-linked micelle
  • HDAC inhibitor
  • Targeted delivery
  • Thailandepsin A

Cite this

Xiao, Kai ; Li, Yuan Pei ; Wang, Cheng ; Ahmad, Sarah ; Vu, Michael ; Kuma, Krishneel ; Cheng, Yi Qiang ; Lam, Kit S. / Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer. In: Biomaterials. 2015 ; Vol. 67. pp. 183-193.
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Disulfide cross-linked micelles of novel HDAC inhibitor thailandepsin A for the treatment of breast cancer. / Xiao, Kai; Li, Yuan Pei; Wang, Cheng; Ahmad, Sarah; Vu, Michael; Kuma, Krishneel; Cheng, Yi Qiang; Lam, Kit S.

In: Biomaterials, Vol. 67, 01.10.2015, p. 183-193.

Research output: Contribution to journalArticle

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AU - Li, Yuan Pei

AU - Wang, Cheng

AU - Ahmad, Sarah

AU - Vu, Michael

AU - Kuma, Krishneel

AU - Cheng, Yi Qiang

AU - Lam, Kit S.

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AB - 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.

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