Download PDF
Planta Med 2015; 81(03): 222-227
DOI: 10.1055/s-0034-1396149
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Aceroside VIII is a New Natural Selective HDAC6 Inhibitor that Synergistically Enhances the Anticancer Activity of HDAC Inhibitor in HT29 Cells

Hyun-Wook Ryu
1   College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
,
Dong-Hun Lee
1   College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
2   Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea
,
Dong-Hee Shin
1   College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
,
Seung Hyun Kim
1   College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
,
So Hee Kwon
1   College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 23 July 2014
revised 31 October 2014

accepted 28 November 2014

Publication Date:
15 January 2015 (online)

Also available at
    Permissions and Reprints

Abstract

The identification of new isoform-specific histone deacetylase inhibitors is important for revealing the biological functions of individual histone deacetylase and for determining their potential use as therapeutic agents. Among the 11 zinc-dependent histone deacetylases that have been identified in humans, histone deacetylase 6 is a structurally and functionally unique enzyme. Here, we tested the inhibitory activity of diarylheptanoids isolated from Betula platyphylla against histone deacetylase 6. Aceroside VIII selectively inhibited histone deacetylase 6 catalytic activity and the combined treatment of aceroside VIII or (−)-centrolobol with A452, another selective histone deacetylase 6 inhibitor, led to a synergistic increase in levels of acetylated α-tubulin. Aceroside VIII, paltyphyllone, and (−)-centrolobol synergistically enhanced the induction of apoptosis and growth inhibition by A452. Consistent with these results, A452 in combination with aceroside VIII, paltyphyllone, or (−)-centrolobol was more potent than either drug alone for the induction of apoptosis. Together, these findings indicate that aceroside VIII is a specific histone deacetylase 6 inhibitor and points to a mechanism by which natural histone deacetylase 6-selective inhibitors may enhance the efficacy of other histone deacetylase 6 inhibitors in colon cancer cells.

Key words

histone deacetylase 6 - HDAC6-selective inhibitor - aceroside VIII - colon cancer - apoptosis - combination therapy
 

  • References

  • 1 Verdel A, Curtet S, Brocard MP, Rousseaux S, Lemercier C, Yoshida M, Khochbin S. Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr Biol 2000; 10: 747-749
    CrossrefPubMedSearch in Google Scholar
  • 2 Boyault C, Gilquin B, Zhang Y, Rybin V, Garman E, Meyer-Klaucke W, Matthias P, Muller CW, Khochbin S. HDAC6-p 97/VCP controlled polyubiquitin chain turnover. Embo J 2006; 25: 3357-3366
    CrossrefPubMedSearch in Google Scholar
  • 3 Hook SS, Orian A, Cowley SM, Eisenman RN. Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc Natl Acad Sci U S A 2002; 99: 13425-13430
    CrossrefPubMedSearch in Google Scholar
  • 4 Seigneurin-Berny D, Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S. Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol Cell Biol 2001; 21: 8035-8044
    CrossrefPubMedSearch in Google Scholar
  • 5 Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K. 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 2005; 280: 26729-26734
    CrossrefPubMedSearch in Google Scholar
  • 6 Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 2003; 100: 4389-4394
    CrossrefPubMedSearch in Google Scholar
  • 7 Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature 2002; 417: 455-458
    CrossrefPubMedSearch in Google Scholar
  • 8 Wood ZA, Poole LB, Karplus PA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 2003; 300: 650-653
    CrossrefPubMedSearch in Google Scholar
  • 9 Li Y, Shin D, Kwon SH. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. Febs J 2013; 280: 775-793
    PubMedSearch in Google Scholar
  • 10 Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, Cao C, Li N, Cheng HL, Chua K, Lombard D, Mizeracki A, Matthias G, Alt FW, Khochbin S, Matthias P. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol 2008; 28: 1688-1701
    CrossrefPubMedSearch in Google Scholar
  • 11 Mehnert JM, Kelly WK. Histone deacetylase inhibitors: biology and mechanism of action. Cancer J 2007; 13: 23-29
    CrossrefPubMedSearch in Google Scholar
  • 12 Richon VM, Garcia-Vargas J, Hardwick JS. Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 2009; 280: 201-210
    CrossrefPubMedSearch in Google Scholar
  • 13 Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 2007; 1: 19-25
    CrossrefPubMedSearch in Google Scholar
  • 14 Campas-Moya C. Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today 2009; 45: 787-795
    CrossrefPubMedSearch in Google Scholar
  • 15 Duvic M, Olsen EA, Breneman D, Pacheco TR, Parker S, Vonderheid EC, Abuav R, Ricker JL, Rizvi S, Chen C, Boileau K, Gunchenko A, Sanz-Rodriguez C, Geskin LJ. Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymphoma Myeloma 2009; 9: 412-416
    CrossrefPubMedSearch in Google Scholar
  • 16 Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotechnol 2007; 25: 84-90
    CrossrefPubMedSearch in Google Scholar
  • 17 Bergman JA, Woan K, Perez-Villarroel P, Villagra A, Sotomayor EM, Kozikowski AP. Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth. J Med Chem 2012; 55: 9891-9899
    CrossrefPubMedSearch in Google Scholar
  • 18 Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo . Cancer Res 2000; 60: 5165-5170
    PubMedSearch in Google Scholar
  • 19 Inks ES, Josey BJ, Jesinkey SR, Chou CJ. A novel class of small molecule inhibitors of HDAC6. ACS Chem Biol 2012; 7: 331-339
    CrossrefPubMedSearch in Google Scholar
  • 20 Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, Jarpe M, van Duzer JH, Mazitschek R, Ogier WC, Cirstea D, Rodig S, Eda H, Scullen T, Canavese M, Bradner J, Anderson KC, Jones SS, Raje N. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012; 119: 2579-2589
    CrossrefPubMedSearch in Google Scholar
  • 21 Smil DV, Manku S, Chantigny YA, Leit S, Wahhab A, Yan TP, Fournel M, Maroun C, Li Z, Lemieux AM, Nicolescu A, Rahil J, Lefebvre S, Panetta A, Besterman JM, Deziel R. Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg Med Chem Lett 2009; 19: 688-692
    CrossrefPubMedSearch in Google Scholar
  • 22 Estiu G, Greenberg E, Harrison CB, Kwiatkowski NP, Mazitschek R, Bradner JE, Wiest O. Structural origin of selectivity in class II-selective histone deacetylase inhibitors. J Med Chem 2008; 51: 2898-2906
    CrossrefPubMedSearch in Google Scholar
  • 23 Dallavalle S, Pisano C, Zunino F. Development and therapeutic impact of HDAC6-selective inhibitors. Biochem Pharmacol 2012; 84: 756-765
    CrossrefPubMedSearch in Google Scholar
  • 24 Huh JE, Baek YH, Kim YJ, Lee JD, Choi DY, Park DS. Protective effects of butanol fraction from Betula platyphyla var. japonica on cartilage alterations in a rabbit collagenase-induced osteoarthritis. J Ethnopharmacol 2009; 123: 515-521
    CrossrefPubMedSearch in Google Scholar
  • 25 Ju EM, Lee SE, Hwang HJ, Kim JH. Antioxidant and anticancer activity of extract from Betula platyphylla var. japonica . Life Sci 2004; 74: 1013-1026
    CrossrefPubMedSearch in Google Scholar
  • 26 Matsuda H, Ishikado A, Nishida N, Ninomiya K, Fujiwara H, Kobayashi Y, Yoshikawa M. Hepatoprotective, superoxide scavenging, and antioxidative activities of aromatic constituents from the bark of Betula platyphylla var. japonica . Bioorg Med Chem Lett 1998; 8: 2939-2944
    CrossrefPubMedSearch in Google Scholar
  • 27 Akihisa T, Taguchi Y, Yasukawa K, Tokuda H, Akazawa H, Suzuki T, Kimura Y. Acerogenin M, a cyclic diarylheptanoid, and other phenolic compounds from Acer nikoense and their anti-inflammatory and anti-tumor-promoting effects. Chem Pharm Bull (Tokyo) 2006; 54: 735-739
    CrossrefPubMedSearch in Google Scholar
  • 28 Lee WH, Loo CY, Young PM, Traini D, Mason RS, Rohanizadeh R. Recent advances in curcumin nanoformulation for cancer therapy. Expert Opin Drug Deliv 2014; 11: 1183-1201
    CrossrefPubMedSearch in Google Scholar
  • 29 Novakovic M, Pesic M, Trifunovic S, Vuckovic I, Todorovic N, Podolski-Renic A, Dinic J, Stojkovic S, Tesevic V, Vajs V, Milosavljevic S. Diarylheptanoids from the bark of black alder inhibit the growth of sensitive and multi-drug resistant non-small cell lung carcinoma cells. Phytochemistry 2014; 97: 46-54
    CrossrefPubMedSearch in Google Scholar
  • 30 Kim SH, Park JH, Kim TB, Lee HH, Lee KY, Kim YC, Sung SH. Inhibition of antigen-induced degranulation by aryl compounds isolated from the bark of Betula platyphylla in RBL-2H3 cells. Bioorg Med Chem Lett 2010; 20: 2824-2827
    CrossrefPubMedSearch in Google Scholar
  • 31 Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769-784
    Search in Google Scholar
  • 32 Choi E, Lee C, Park JE, Seo JJ, Cho M, Kang JS, Kim HM, Park SK, Lee K, Han G. Structure and property based design, synthesis and biological evaluation of gamma-lactam based HDAC inhibitors. Bioorg Med Chem Lett 2011; 21: 1218-1221
    CrossrefPubMedSearch in Google Scholar
  • 33 Chou T. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010; 70: 440-446
    CrossrefPubMedSearch in Google Scholar
  • 34 Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares AH, Smulson ME. Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis. J Biol Chem 1998; 273: 13703-13712
    CrossrefPubMedSearch in Google Scholar
  • 35 Namdar M, Perez G, Ngo L, Marks PA. Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc Natl Acad Sci U S A 2010; 107: 20003-20008
    CrossrefPubMedSearch in Google Scholar
  • 36 Lee KY, Jeong EJ, Huh J, Cho N, Kim TB, Jeon BJ, Kim SH, Kim HP, Sung SH. Cognition-enhancing and neuroprotective activities of the standardized extract of Betula platyphylla bark and its major diarylheptanoids. Phytomedicine 2012; 19: 1315-1320
    CrossrefPubMedSearch in Google Scholar
  • 37 Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005; 18: 601-607
    CrossrefPubMedSearch in Google Scholar