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


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.


Anti-cancer drug Caspase Docetaxel Histone deacetylase inhibitor Prostate cancer 



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).


  1. 1.
    Johnstone RW, Licht JD (2003) Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4(1):13–18CrossRefPubMedGoogle Scholar
  2. 2.
    Acharya MR, Sparreboom A, Venitz J, Figg WD (2005) Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol Pharmacol 68(4):917–932. doi: 10.1124/mol.105.014167 CrossRefPubMedGoogle Scholar
  3. 3.
    Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51. doi: 10.1038/nrc1779 CrossRefPubMedGoogle Scholar
  4. 4.
    Glaser KB (2007) HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol 74(5):659–671. doi: 10.1016/j.bcp.2007.04.007 CrossRefPubMedGoogle Scholar
  5. 5.
    Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, Hu J, Dzik-Jurasz A, Yang W, Scher HI (2010) A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 66(1):181–189. doi: 10.1007/s00280-010-1289-x CrossRefPubMedGoogle Scholar
  6. 6.
    Reid T, Thorne S, Hedjran F, Lee YL, Eng L (2005) Impact of the histone deacetylase inhibitors on Taxotere resistance due to P-gp (MDR) and Tubulin Acetylation Proc Amer Assoc Cancer Res 46 (Abstract #6158)Google Scholar
  7. 7.
    Daugaard G, Fizazi K, Huebner G, Braumann D, Rubinsak JR, Allouache D, Rodriguez GI, Stahl M, Fuglsang L, Hainsworth JD (2010) An open-label randomized phase II trial of belinostat (PXD101) in combination with carboplatin and paclitaxel (BelCaP) compared to carboplatin and paclitaxel in patients with previously untreated carcinoma of unknown primary. J Clin Oncol 28: Absract No TPS185Google Scholar
  8. 8.
    Hwang JJ, Kim YS, Kim MJ, Kim DE, Jeong IG, Kim CS (2010) Histone deacetylase inhibitor potentiates anticancer effect of docetaxel via modulation of Bcl-2 family proteins and tubulin in hormone refractory prostate cancer cells. J Urol 184(6):2557–2564. doi: 10.1016/j.juro.2010.07.035 CrossRefPubMedGoogle Scholar
  9. 9.
    Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A, Altucci L, Nervi C, Minucci S, Pelicci PG (2005) Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11(1):71–76. doi: 10.1038/nm1160 CrossRefPubMedGoogle Scholar
  10. 10.
    Abbas A, Gupta S (2008) The role of histone deacetylases in prostate cancer. Epigenetics 3(6):300–309CrossRefPubMedGoogle Scholar
  11. 11.
    Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26(37):5541–5552. doi: 10.1038/sj.onc.1210620 CrossRefPubMedGoogle Scholar
  12. 12.
    Mai A, Massa S, Rotili D, Cerbara I, Valente S, Pezzi R, Simeoni S, Ragno R (2005) Histone deacetylation in epigenetics: an attractive target for anticancer therapy. Med Res Rev 25(3):261–309. doi: 10.1002/med.20024 CrossRefPubMedGoogle Scholar
  13. 13.
    Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 100(8):4389–4394. doi: 10.1073/pnas.0430973100 CrossRefPubMedGoogle Scholar
  14. 14.
    Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29):26729–26734. doi: 10.1074/jbc.C500186200 CrossRefPubMedGoogle Scholar
  15. 15.
    Subramanian C, Opipari AW Jr, Bian X, Castle VP, Kwok RP (2005) Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102(13):4842–4847. doi: 10.1073/pnas.0408351102 CrossRefPubMedGoogle Scholar
  16. 16.
    Thelen P, Schweyer S, Hemmerlein B, Wuttke W, Seseke F, Ringert RH (2004) Expressional changes after histone deacetylase inhibition by valproic acid in LNCaP human prostate cancer cells. Int J Oncol 24(1):25–31PubMedGoogle Scholar
  17. 17.
    Qian DZ, Wei YF, Wang X, Kato Y, Cheng L, Pili R (2007) Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. Prostate 67(11):1182–1193. doi: 10.1002/pros.20611 CrossRefPubMedGoogle Scholar
  18. 18.
    D’Acunto CW, Fontanella B, Rodriquez M, Taddei M, Parente L, Petrella A (2010) Histone deacetylase inhibitor FR235222 sensitizes human prostate adenocarcinoma cells to apoptosis through up-regulation of Annexin A1. Cancer Lett 295(1):85–91. doi: 10.1016/j.canlet.2010.02.016 CrossRefPubMedGoogle Scholar
  19. 19.
    Qian X, Ara G, Mills E, LaRochelle WJ, Lichenstein HS, Jeffers M (2008) Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer 122(6):1400–1410. doi: 10.1002/ijc.23243 CrossRefPubMedGoogle Scholar
  20. 20.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300. doi: 10.3322/caac.20073 CrossRefPubMedGoogle Scholar
  21. 21.
    Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351(15):1513–1520. doi: 10.1056/NEJMoa041318 CrossRefPubMedGoogle Scholar
  22. 22.
    Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512. doi: 10.1056/NEJMoa040720 CrossRefPubMedGoogle Scholar
  23. 23.
    Galsky MD, Vogelzang NJ (2010) Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol 21(11):2135–2144. doi: 10.1093/annonc/mdq050 CrossRefPubMedGoogle Scholar
  24. 24.
    Oh ET, Park MT, Choi BH, Ro S, Choi EK, Jeong SY, Park HJ (2010) Novel histone deacetylase inhibitor CG200745 induces clonogenic cell death by modulating acetylation of p53 in cancer cells. Invest New Drugs. doi: 10.1007/s10637-010-9568-2
  25. 25.
    Di Lorenzo G, Figg WD, Fossa SD, Mirone V, Autorino R, Longo N, Imbimbo C, Perdona S, Giordano A, Giuliano M, Labianca R, De Placido S (2008) Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 54(5):1089–1094. doi: 10.1016/j.eururo.2008.01.082 CrossRefPubMedGoogle Scholar
  26. 26.
    Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21):7291–7300PubMedGoogle Scholar
  27. 27.
    Chen Y, Sawyers CL, Scher HI (2008) Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol 8(4):440–448. doi: 10.1016/j.coph.2008.07.005 CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang Z, Stanfield J, Frenkel E, Kabbani W, Hsieh JT (2007) Enhanced therapeutic effect on androgen-independent prostate cancer by depsipeptide (FK228), a histone deacetylase inhibitor, in combination with docetaxel. Urology 70(2):396–401. doi: 10.1016/j.urology.2007.03.052 CrossRefPubMedGoogle Scholar
  29. 29.
    Kanzaki M, Kakinuma H, Kumazawa T, Inoue T, Saito M, Narita S, Yuasa T, Tsuchiya N, Habuchi T (2007) Low concentrations of the histone deacetylase inhibitor, depsipeptide, enhance the effects of gemcitabine and docetaxel in hormone refractory prostate cancer cells. Oncol Rep 17(4):761–767PubMedGoogle Scholar
  30. 30.
    Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2(10):971–984PubMedGoogle Scholar
  31. 31.
    Ramalingam SS, Parise RA, Ramanathan RK, Lagattuta TF, Musguire LA, Stoller RG, Potter DM, Argiris AE, Zwiebel JA, Egorin MJ, Belani CP (2007) Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 13(12):3605–3610. doi: 10.1158/1078-0432.CCR-07-0162 CrossRefPubMedGoogle Scholar
  32. 32.
    Schneider BJ, Kalemkerian GP, Bradley D, Smith DC, Egorin MJ, Daignault S, Dunn R, Hussain M (2010) Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies. Invest New Drugs. doi: 10.1007/s10637-010-9503-6

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

Personalised recommendations