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Investigational New Drugs

, Volume 30, Issue 4, pp 1434–1442 | Cite as

A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL

  • Jung Jin Hwang
  • Yong Sook Kim
  • Taelim Kim
  • Mi Joung Kim
  • In Gab Jeong
  • Je-Hwan Lee
  • Jene Choi
  • Sejin Jang
  • Seonggu Ro
  • Choung-Soo KimEmail author
PRECLINICAL STUDIES

Summary

We synthesized a novel hydroxamate-based pan-histone deacetylase inhibitor (HDACI), CG200745 {(E)-2-(Naphthalen-1-yloxymethyl)-oct-2-enedioic acid 1-[(3-dimethylamino-propyl)-amide] 8-hydroxyamide]}. Like other inhibitors, for example vorinostat and belinostat, CG200745 has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. Firstly, we analyzed its inhibitory activity against histone deacetylase (HDAC) in hormone-dependent LNCaP cells and hormone-independent DU145 and PC3 cells. CG200745 inhibited deacetylation of histone H3 and tubulin as much as vorinostat and belinostat did. CG200745 also inhibited growth of prostate cancer cells, increased sub-G1 population, and activated caspase-9, -3 and −8 in LNCaP, DU145 and PC3 cells. These results indicate that CG200745 induces apoptosis. Next, we examined the effect of CG200745 on cell death induced by docetaxel in DU145 cells in vitro and in vivo. Compared to mono-treatment with each drug, pre-treatment of DU145 cells with docetaxel followed by CG200745 showed synergistic cytotoxicity, and increased the apoptotic sub-G1 population, caspase activation, and tubulin acetylation. Moreover, the combination treatment decreased Mcl-1 and Bcl-XL. Docetaxel and CG200745 combination reduced tumor size in the DU145 xenograft model. These preclinical results show that combination treatment with docetaxel and new HDACI, CG200745, potentiated anti-tumor effect in hormone-refractory prostate cancer (HRPC) cells via activation of apoptosis.

Keywords

Anti-cancer drug Caspase Docetaxel Histone deacetylase inhibitor Prostate cancer 

Notes

Acknowledgement

Vorinostat, belinostat and CG0005 were synthesized by CrystalGenomics Inc. This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea. (A062254).

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jung Jin Hwang
    • 1
  • Yong Sook Kim
    • 1
  • Taelim Kim
    • 1
  • Mi Joung Kim
    • 1
  • In Gab Jeong
    • 2
  • Je-Hwan Lee
    • 1
    • 3
  • Jene Choi
    • 1
    • 4
  • Sejin Jang
    • 1
    • 4
  • Seonggu Ro
    • 1
    • 5
  • Choung-Soo Kim
    • 1
    • 2
    Email author
  1. 1.Institute for Innovative Cancer ResearchUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulSouth Korea
  2. 2.Department of Urology & IICRUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulSouth Korea
  3. 3.Department of Internal Medicine & Laboratory MedicineUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulSouth Korea
  4. 4.Department of PathologyUniversity of Ulsan College of Medicine, Asan Medical CenterSeoulSouth Korea
  5. 5.CrystalGenomics, Inc.SeoulSouth Korea

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