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

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A Correction to this article was published on 02 April 2019

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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.

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Change history

  • 02 April 2019

    The blots of control and docetaxel for caspase-9, caspase-3, caspase-8, Bcl-XL, and tubulin in the Figure 4f were reused from Figure 4 of our previous paper published in Journal of Urology in 2010 (https://doi.org/10.1016/j.juro.2010.07.035).

  • 02 April 2019

    The blots of control and docetaxel for caspase-9, caspase-3, caspase-8, Bcl-XL, and tubulin in the Figure 4f were reused from Figure 4 of our previous paper published in Journal of Urology in 2010 (https://doi.org/10.1016/j.juro.2010.07.035).

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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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Authors and Affiliations

  1. Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 138-736, South Korea

    Jung Jin Hwang, Yong Sook Kim, Taelim Kim, Mi Joung Kim, Je-Hwan Lee, Jene Choi, Sejin Jang, Seonggu Ro & Choung-Soo Kim

  2. Department of Urology & IICR, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-Dong Songpa-Gu, Seoul, 138-736, South Korea

    In Gab Jeong & Choung-Soo Kim

  3. Department of Internal Medicine & Laboratory Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 138-736, South Korea

    Je-Hwan Lee

  4. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 138-736, South Korea

    Jene Choi & Sejin Jang

  5. CrystalGenomics, Inc., 6F, 2nd Building of Asan Institute for Life sciences, Seoul, 138-736, South Korea

    Seonggu Ro

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  1. Jung Jin Hwang
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Hwang, J.J., Kim, Y.S., Kim, T. et al. A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL . Invest New Drugs 30, 1434–1442 (2012). https://doi.org/10.1007/s10637-011-9718-1

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