Investigational New Drugs

, Volume 30, Issue 5, pp 1887–1898 | Cite as

A new synthetic HDAC inhibitor, MHY218, induces apoptosis or autophagy-related cell death in tamoxifen-resistant MCF-7 breast cancer cells

  • Ji Hye Park
  • Mee Young Ahn
  • Tae Hyung Kim
  • Sungpill Yoon
  • Keon Wook Kang
  • Jaewon Lee
  • Hyung Ryong Moon
  • Jee H. Jung
  • Hae Young Chung
  • Hyung Sik Kim
PRECLINICAL STUDIES

Summary

Acquired resistance to tamoxifen (Tam) is a critical problem in breast cancer therapy. Therefore, new potential strategies for Tam-resistant breast cancer are needed recently. In this study, we synthesized a novel histone deacetylase (HDAC) inhibitor, MHY218, for the development of potent inhibitors of HDAC and evaluated its biological activities by monitoring the anticancer effects in Tam-resistant MCF-7 (TAMR/MCF-7) cells via in vitro and in vivo studies. MHY218 significantly inhibited the proliferation of TAMR/MCF-7 cells in a dose-dependent manner. The total HDAC enzyme activity was significantly inhibited, corresponding with inhibition of acetylated H3 and H4 expression in TAMR/MCF-7 cells. HDAC1, 4, and 6 expression levels were decreased in response to MHY218 treatment. Cell cycle analysis indicated that MHY218 induced G2/M phase cell cycle arrest. As expected, apoptotic cell death was observed in response to MHY218 treatment. Interestingly, levels of beclin-1 and LC3-II, the markers of autophagy, were increased in TAMR/MCF-7 cells treated with MHY218. The efficacy of MHY218 was also compared with that of SAHA in vivo in a xenograft model of nude mice bearing a TAMR/MCF-7 cells. MHY218 (10 mg/kg, twice a week for 21 days) completely inhibited tumor growth and MHY218 markedly inhibited the expression of proliferative cell nuclear antigen (PCNA) in tumor tissue. These results indicate that MHY218 can induce caspase-independent autophagic cell death rather than apoptotic cell death. The MHY218-induced autophagic cell death could be a new strategy in the treatment of Tam-resistant human breast cancer.

Keywords

HDAC inhibitor Tamoxifen-resistant Breast cancer Apoptosis Autophagy 

Abbreviations

Tam

Tamoxifen

HDAC

Histone deacetylase

SAHA

Suberoylanilide hydroxamic acid

DMSO

Dimethyl sulfoxide

TAMR/MCF-7

Tamoxifen-resistant MCF-7

EBCTCG

Early Breast Cancer Trialists’ Collaborative Groups

PKA

Protein kinase A

FBS

Fetal bovine serum

SDS

Sodium dodecylsulfate

MTT

3(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide N-acetylcysteine

PI

Propidium iodide

PARP

Poly-ADP ribose polymerase

PBS

Phosphate-buffered saline

PVDF

Polyvinylidene difluoride

ECL

Enhanced chemiluminescence

TsA

Trichostatin A

DAPI

4,6-diamidino-2-phenylindole

HRP

Horseradish peroxidase

IC50

50% inhibitory concentration

CDK

Cyclin-dependent kinase

PCNA

Proliferative cell nuclear antigen

SDS-PAGE

Sodium dodecylsulfate gel electrophoresis

SPF

Specific pathogen free

Supplementary material

10637_2011_9752_MOESM1_ESM.jpg (175 kb)
Supplementary Fig. 1Monodansylcadaverine (MDC) staining shows autophagy was activated in TAMR/MCF-7 cells after treatment with MHY218. Cultured cells were incubated with indicated concentration of drugs for 24 h, fixed with 3.7% paraformaldehyde and then stained with 0.05 mM MDC. Cells were examined by Zeiss confocal microscope LSM 510. Scale bar = 10 μm. Fluorescence particles with blue dots show autophagic vacuoles. The data shown are representative of three independent experiments. (JPEG 174 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ji Hye Park
    • 1
  • Mee Young Ahn
    • 1
  • Tae Hyung Kim
    • 1
  • Sungpill Yoon
    • 2
  • Keon Wook Kang
    • 3
  • Jaewon Lee
    • 1
  • Hyung Ryong Moon
    • 1
  • Jee H. Jung
    • 1
  • Hae Young Chung
    • 1
  • Hyung Sik Kim
    • 1
  1. 1.College of Pharmacy and MRC CenterPusan National UniversityBusanRepublic of Korea
  2. 2.Research Institute, National Cancer CenterGyeonggi-doRepublic of Korea
  3. 3.College of PharmacySeoul National UniversitySeoulRepublic of Korea

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