The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines
Tóm tắt
High histone deacetylase (HDAC) 8 and HDAC10 expression levels have been identified as predictors of exceptionally poor outcomes in neuroblastoma, the most common extracranial solid tumor in childhood. HDAC8 inhibition synergizes with retinoic acid treatment to induce neuroblast maturation in vitro and to inhibit neuroblastoma xenograft growth in vivo. HDAC10 inhibition increases intracellular accumulation of chemotherapeutics through interference with lysosomal homeostasis, ultimately leading to cell death in cultured neuroblastoma cells. So far, no HDAC inhibitor covering HDAC8 and HDAC10 at micromolar concentrations without inhibiting HDACs 1, 2 and 3 has been described. Here, we introduce TH34 (3-(N-benzylamino)-4-methylbenzhydroxamic acid), a novel HDAC6/8/10 inhibitor for neuroblastoma therapy. TH34 is well-tolerated by non-transformed human skin fibroblasts at concentrations up to 25 µM and modestly impairs colony growth in medulloblastoma cell lines, but specifically induces caspase-dependent programmed cell death in a concentration-dependent manner in several human neuroblastoma cell lines. In addition to the induction of DNA double-strand breaks, HDAC6/8/10 inhibition also leads to mitotic aberrations and cell-cycle arrest. Neuroblastoma cells display elevated levels of neuronal differentiation markers, mirrored by formation of neurite-like outgrowths under maintained TH34 treatment. Eventually, after long-term treatment, all neuroblastoma cells undergo cell death. The combination of TH34 with plasma-achievable concentrations of retinoic acid, a drug applied in neuroblastoma therapy, synergistically inhibits colony growth (combination index (CI) < 0.1 for 10 µM of each). In summary, our study supports using selective HDAC inhibitors as targeted antineoplastic agents and underlines the therapeutic potential of selective HDAC6/8/10 inhibition in high-grade neuroblastoma.
Tài liệu tham khảo
Adamson PC (1996) All-trans-retinoic acid pharmacology and its impact on the treatment of acute promyelocytic leukemia. Oncologist 1(5):305–314
Balasubramanian S, Verner E, Buggy JJ (2009) Isoform-specific histone deacetylase inhibitors: the next step? Cancer Lett 280(2):211–221. https://doi.org/10.1016/j.canlet.2009.02.013
Bates SE, Eisch R, Ling A et al (2015) Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data. Br J Haematol 170(1):96–109. https://doi.org/10.1111/bjh.13400
Beckouet F, Hu B, Roig MB et al (2010) An Smc3 acetylation cycle is essential for establishment of sister chromatid cohesion. Mol Cell 39(5):689–699. https://doi.org/10.1016/j.molcel.2010.08.008
Beckouet F, Srinivasan M, Roig MB et al (2016) Releasing activity disengages cohesin’s Smc3/Scc1 interface in a process blocked by acetylation. Mol Cell 61(4):563–574. https://doi.org/10.1016/j.molcel.2016.01.026
Bradner JE, West N, Grachan ML et al (2010) Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6(3):238–243. https://doi.org/10.1038/nchembio.313
Brodeur GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3(3):203–216. https://doi.org/10.1038/nrc1014
Caron P, Aymard F, Iacovoni JS et al (2012) Cohesin protects genes against gamma H2AX induced by DNA double-strand breaks. PLoS Genet 8(1):e1002460. https://doi.org/10.1371/journal.pgen.1002460
Cheng T, Grasse L, Shah J, Chandra J (2015) Panobinostat, a pan-histone deacetylase inhibitor: rationale for and application to treatment of multiple myeloma. Drugs Today (Barc) 51(8):491–504. https://doi.org/10.1358/dot.2015.51.8.2362311
Cheung NK, Dyer MA (2013) Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer 13(6):397–411. https://doi.org/10.1038/nrc3526
Chou TC (2010) Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res 70(2):440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370(Pt 3):737–749. https://doi.org/10.1042/BJ20021321
Deardorff MA, Bando M, Nakato R et al (2012) HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489(7415):313–317. https://doi.org/10.1038/nature11316
Decroos C, Christianson NH, Gullett LE et al (2015) Biochemical and structural characterization of HDAC8 mutants associated with Cornelia de Lange syndrome spectrum disorders. Biochemistry 54(42):6501–6513. https://doi.org/10.1021/acs.biochem.5b00881
Ecker J, Oehme I, Mazitschek R et al (2015) Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol Commun 3:22. https://doi.org/10.1186/s40478-015-0201-7
El-Deiry WS, Tokino T, Velculescu VE et al (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75(4):817–825
Feuerstein BG, Pattabiraman N, Marton LJ (1990) Molecular mechanics of the interactions of spermine with DNA: DNA bending as a result of ligand binding. Nucleic Acids Res 18(5):1271–1282
Fischer DD, Cai R, Bhatia U et al (2002) Isolation and characterization of a novel class II histone deacetylase, HDAC10. J Biol Chem 277(8):6656–6666. https://doi.org/10.1074/jbc.M108055200
Fischer M, Skowron M, Berthold F (2005) Reliable transcript quantification by real-time reverse transcriptase-polymerase chain reaction in primary neuroblastoma using normalization to averaged expression levels of the control genes HPRT1 and SDHA. J Mol Diagn 7(1):89–96
Gamble LD, Hogarty MD, Liu X et al (2012) Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma. Front Oncol 2:162. https://doi.org/10.3389/fonc.2012.00162
Gartel AL, Tyner AL (1999) Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res 246(2):280–289. https://doi.org/10.1006/excr.1998.4319
Gligoris TG, Scheinost JC, Burmann F et al (2014) Closing the cohesin ring: structure and function of its Smc3-kleisin interface. Science 346(6212):963–967. https://doi.org/10.1126/science.1256917
Hai Y, Shinsky SA, Porter NJ, Christianson DW (2017) Histone deacetylase 10 structure and molecular function as a polyamine deacetylase. Nat Commun 8:15368. https://doi.org/10.1038/ncomms15368
Heimburg T, Chakrabarti A, Lancelot J et al (2016) Structure-based design and synthesis of novel inhibitors targeting HDAC8 from Schistosoma mansoni for the treatment of schistosomiasis. J Med Chem 59(6):2423–2435. https://doi.org/10.1021/acs.jmedchem.5b01478
Heimburg T, Kolbinger FR, Zeyen P et al (2017) Structure-based design and biological characterization of selective histone deacetylase 8 (HDAC8) inhibitors with anti-neuroblastoma activity. J Med Chem. https://doi.org/10.1021/acs.jmedchem.7b01447
Hogarty MD, Norris MD, Davis K et al (2008) ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Res 68(23):9735–9745. https://doi.org/10.1158/0008-5472.CAN-07-6866
Hosoya N, Miyagawa K (2014) Targeting DNA damage response in cancer therapy. Cancer Sci 105(4):370–388. https://doi.org/10.1111/cas.12366
Islam MM, Banerjee T, Packard CZ et al (2017) HDAC10 as a potential therapeutic target in ovarian cancer. Gynecol Oncol 144(3):613–620. https://doi.org/10.1016/j.ygyno.2017.01.009
Jung YS, Qian Y, Chen X (2010) Examination of the expanding pathways for the regulation of p21 expression and activity. Cell Signal 22(7):1003–1012. https://doi.org/10.1016/j.cellsig.2010.01.013
Kalin JH, Butler KV, Akimova T, Hancock WW, Kozikowski AP (2012) Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3 + T-regulatory cells. J Med Chem 55(2):639–651. https://doi.org/10.1021/jm200773h
Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115(6):727–738
Kim MS, Kwon HJ, Lee YM et al (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7(4):437–443. https://doi.org/10.1038/86507
Koeneke E, Witt O, Oehme I (2015) HDAC family members intertwined in the regulation of autophagy: a druggable vulnerability in aggressive tumor entities. Cells 4(2):135–168. https://doi.org/10.3390/cells4020135
Kramer OH, Mahboobi S, Sellmer A (2014) Drugging the HDAC6-HSP90 interplay in malignant cells. Trends Pharmacol Sci 35(10):501–509. https://doi.org/10.1016/j.tips.2014.08.001
Lane AA, Chabner BA (2009) Histone deacetylase inhibitors in cancer therapy. J Clin Oncol 27(32):5459–5468. https://doi.org/10.1200/JCO.2009.22.1291
Lastowska M, Viprey V, Santibanez-Koref M et al (2007) Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data. Oncogene 26(53):7432–7444. https://doi.org/10.1038/sj.onc.1210552
Lee JH, Choy ML, Ngo L, Foster SS, Marks PA (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci USA 107(33):14639–14644. https://doi.org/10.1073/pnas.1008522107
Li Z, Zhu WG (2014) Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int J Biol Sci 10(7):757–770. https://doi.org/10.7150/ijbs.9067
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262
Lopez JE, Haynes SE, Majmudar JD, Martin BR, Fierke CA (2017) HDAC8 substrates identified by genetically encoded active site photocrosslinking. J Am Chem Soc 139(45):16222–16227. https://doi.org/10.1021/jacs.7b07603
Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287–294. https://doi.org/10.1038/nature10760
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12(10):1247–1252. https://doi.org/10.1634/theoncologist.12-10-1247
Mariotti LG, Pirovano G, Savage KI et al (2013) Use of the gamma-H2AX assay to investigate DNA repair dynamics following multiple radiation exposures. PLoS One 8(11):e79541. https://doi.org/10.1371/journal.pone.0079541
Matthews HR (1993) Polyamines, chromatin structure and transcription. Bioessays 15(8):561–566. https://doi.org/10.1002/bies.950150811
Miller KM, Tjeertes JV, Coates J et al (2010) Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol 17(9):1144–1151. https://doi.org/10.1038/nsmb.1899
Muslimovic A, Ismail IH, Gao Y, Hammarsten O (2008) An optimized method for measurement of gamma-H2AX in blood mononuclear and cultured cells. Nat Protoc 3(7):1187–1193. https://doi.org/10.1038/nprot.2008.93
Namdar M, Perez G, Ngo L, Marks PA (2010) Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc Natl Acad Sci USA 107(46):20003–20008. https://doi.org/10.1073/pnas.1013754107
Nikolova T, Kiweler N, Kramer OH (2017) Interstrand crosslink repair as a target for HDAC inhibition. Trends Pharmacol Sci 38(9):822–836. https://doi.org/10.1016/j.tips.2017.05.009
Nishiyama T, Ladurner R, Schmitz J et al (2010) Sororin mediates sister chromatid cohesion by antagonizing Wapl. Cell 143(5):737–749. https://doi.org/10.1016/j.cell.2010.10.031
O’Connor OA, Horwitz S, Masszi T et al (2015) Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) Study. J Clin Oncol 33(23):2492–2499. https://doi.org/10.1200/JCO.2014.59.2782
Oehme I, Bosser S, Zornig M (2006) Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO. Cell Death Differ 13(2):189–201. https://doi.org/10.1038/sj.cdd.4401730
Oehme I, Deubzer HE, Lodrini M, Milde T, Witt O (2009a) Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert Opin Investig Drugs 18(11):1605–1617. https://doi.org/10.1517/14728220903241658
Oehme I, Deubzer HE, Wegener D et al (2009b) Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res Off J Am Assoc Cancer Res 15(1):91–99. https://doi.org/10.1158/1078-0432.CCR-08-0684
Oehme I, Linke JP, Bock BC et al (2013) Histone deacetylase 10 promotes autophagy-mediated cell survival. Proc Natl Acad Sci USA 110(28):E2592-601. https://doi.org/10.1073/pnas.1300113110
Pajtler KW, Mahlow E, Odersky A et al (2014) Neuroblastoma in dialog with its stroma: NTRK1 is a regulator of cellular cross-talk with Schwann cells. Oncotarget 5(22):11180–11192. https://doi.org/10.18632/oncotarget.2611
Pang X, He G, Luo C, Wang Y, Zhang B (2016) Knockdown of Rad9A enhanced DNA damage induced by trichostatin A in esophageal cancer cells. Tumor Biol 37(1):9639–9670. https://doi.org/10.1007/s13277-015-3879-z
Park JH, Kim SH, Choi MC et al (2008) Class II histone deacetylases play pivotal roles in heat shock protein 90-mediated proteasomal degradation of vascular endothelial growth factor receptors. Biochem Biophys Res Commun 368(2):318–322. https://doi.org/10.1016/j.bbrc.2008.01.056
Pinto NR, Applebaum MA, Volchenboum SL et al (2015) Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol 33(27):3008–3017. https://doi.org/10.1200/JCO.2014.59.4648
Radhakrishnan R, Li Y, Xiang S et al (2015) Histone deacetylase 10 regulates DNA mismatch repair and may involve the deacetylation of MutS homolog 2. J Biol Chem 290(37):22795–22804. https://doi.org/10.1074/jbc.M114.612945
Rettig I, Koeneke E, Trippel F et al (2015) Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. Cell Death Dis 6:e1657. https://doi.org/10.1038/cddis.2015.24
PDQ Pediatric Treatment Editorial Board, PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US) (2002–2017) Neuroblastoma Treatment (PDQ®): Health Professional Version
Robers MB, Dart ML, Woodroofe CC et al (2015) Target engagement and drug residence time can be observed in living cells with BRET. Nat Commun 6:10091. https://doi.org/10.1038/ncomms10091
Robert C, Nagaria PK, Pawar N et al (2016) Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin. Leuk Res 45:14–23. https://doi.org/10.1016/j.leukres.2016.03.007
Rogakou EP, Nieves-Neira W, Boon C, Pommier Y, Bonner WM (2000) Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. J Biol Chem 275(13):9390–9395
Santo L, Hideshima T, Kung AL et al (2012) Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119(11):2579–2589. https://doi.org/10.1182/blood-2011-10-387365
Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671–675
Schramm A, Schowe B, Fielitz K et al (2012) Exon-level expression analyses identify MYCN and NTRK1 as major determinants of alternative exon usage and robustly predict primary neuroblastoma outcome. Br J Cancer 107(8):1409–1417. https://doi.org/10.1038/bjc.2012.391
Shi Y, Dong M, Hong X et al (2015) Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol 26(8):1766–1771. https://doi.org/10.1093/annonc/mdv237
Uhlmann F (2016) SMC complexes: from DNA to chromosomes. Nat Rev Mol Cell Biol 17(7):399–412. https://doi.org/10.1038/nrm.2016.30
Vashishta A, Hetman M (2014) Inhibitors of histone deacetylases enhance neurotoxicity of DNA damage. Neuromol Med 16(4):727–741. https://doi.org/10.1007/s12017-014-8322-x
Vogl DT, Raje N, Jagannath S et al (2017) Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin Cancer Res Off J Am Assoc Cancer Res 23(13):3307–3315. https://doi.org/10.1158/1078-0432.CCR-16-2526
Wang L, Xiang S, Williams KA et al (2012) Depletion of HDAC6 enhances cisplatin-induced DNA damage and apoptosis in non-small cell lung cancer cells. PLoS One 7(9):e44265. https://doi.org/10.1371/journal.pone.0044265
Ward E, DeSantis C, Robbins A, Kohler B, Jemal A (2014) Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64(2):83–103. https://doi.org/10.3322/caac.21219
Watrin E, Peters JM (2009) The cohesin complex is required for the DNA damage-induced G2/M checkpoint in mammalian cells. EMBO J 28(17):2625–2635. https://doi.org/10.1038/emboj.2009.202
Witt O, Monkemeyer S, Ronndahl G et al (2003) Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood 101(5):2001–2007. https://doi.org/10.1182/blood-2002-08-2617
Witt O, Deubzer HE, Lodrini M, Milde T, Oehme I (2009a) Targeting histone deacetylases in neuroblastoma. Curr Pharm Des 15(4):436–447
Witt O, Deubzer HE, Milde T, Oehme I (2009b) HDAC family: what are the cancer relevant targets? Cancer Lett 277(1):8–21. https://doi.org/10.1016/j.canlet.2008.08.016
Yang XJ, Seto E (2008) The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9(3):206–218. https://doi.org/10.1038/nrm2346
Yee AJ, Bensinger WI, Supko JG et al (2016) Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol 17(11):1569–1578. https://doi.org/10.1016/S1470-2045(16)30375-8