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


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.


HDAC inhibitor Tamoxifen-resistant Breast cancer Apoptosis Autophagy 





Histone deacetylase


Suberoylanilide hydroxamic acid


Dimethyl sulfoxide


Tamoxifen-resistant MCF-7


Early Breast Cancer Trialists’ Collaborative Groups


Protein kinase A


Fetal bovine serum


Sodium dodecylsulfate


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


Propidium iodide


Poly-ADP ribose polymerase


Phosphate-buffered saline


Polyvinylidene difluoride


Enhanced chemiluminescence


Trichostatin A




Horseradish peroxidase


50% inhibitory concentration


Cyclin-dependent kinase


Proliferative cell nuclear antigen


Sodium dodecylsulfate gel electrophoresis


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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