Advertisement

Resistance to Histone Deacetylase Inhibitors in the Treatment of Lymphoma

  • Allyson FlowerEmail author
  • Oussama Abla
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 21)

Abstract

Outcomes for patients with lymphoma have improved through the use of chemo/immunotherapy. However, therapy for patients with advanced disease and relapsed/refractory disease remains inadequate. In addition, off target side effects result in significant short and long-term toxicity. The use of targeted molecular therapy introduces an opportunity for improvement in efficacy and reduction in undesirable off target effects. Histone Deacetylase (HDAC) inhibitors are a class of targeted molecular therapies that have been extensively evaluated for the treatment of refractory malignancies including subtypes of lymphoma. However, critical resistance mechanisms are well described. Optimal efficacy of HDAC inhibitors in the treatment of lymphoma is dependent upon successful strategies to overcome drug resistance.

Keywords

Lymphoma Histone deacetylase inhibitor Resistance Epigenetics 

Abbreviations

AITL

Angioimmunoblastic T-Cell Lymphoma

AML

Acute Myeloid Leukemia

CHOP

Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

CR

Complete Response

CTCL

Cutaneous T-Cell Lymphoma

DLBCL

Diffuse Large B-Cell Lymphoma

ER

Endoplasmic Reticulum

FDA

Food and Drug Administration

FL

Follicular Lymphoma

HAT

Histone acetyltransferase

HDAC

Histone Deacetylase

HDACi

HDAC inhibitors

HL

Hodgkin Lymphoma

MCL

Mantle Cell Lymphoma

MM

Multiple Myeloma

MZL

Marginal Zone Lymphoma

NAD

Nicotinamide Adenine Dinucleotide

NHL

Non-Hodgkin Lymphoma

OR

Overall Response

ORR

Overall Response Rate

PCTCL

Primary Cutaneous T-Cell Lymphoma

PFS

Progression-Free Survival

PR

Partial Response

PTCL

Peripheral T-Cell Lymphoma

r/r

relapsed/refractory

SLL

Small Lymphocytic Lymphoma

Notes

Acknowledgements

AF reviewed the literatures, developed the design of the paper and wrote the manuscript. OA critically revised the manuscript and have approved the final version for publication. The authors would like to thank Erin Morris, RN for her excellent assistance with the preparation of this manuscript.

Disclosure of Conflict of Interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Hochberg J, Flower A, Brugieres L, Cairo MS. NHL in adolescents and young adults: a unique population. Pediatr Blood Cancer. 2018;65(8):e27073.PubMedCrossRefGoogle Scholar
  2. 2.
    Flerlage JE, Metzger ML, Bhakta N. The management of Hodgkin lymphoma in adolescents and young adults: burden of disease or burden of choice? Blood. 2018;132(4):376–84.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol. 2002;2(12):920–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Marquard L, Gjerdrum LM, Christensen IJ, Jensen PB, Sehested M, Ralfkiaer E. Prognostic significance of the therapeutic targets histone deacetylase 1, 2, 6 and acetylated histone H4 in cutaneous T-cell lymphoma. Histopathology. 2008;53(3):267–77.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Marquard L, Poulsen CB, Gjerdrum LM, de Nully Brown P, Christensen IJ, Jensen PB, et al. Histone deacetylase 1, 2, 6 and acetylated histone H4 in B- and T-cell lymphomas. Histopathology. 2009;54(6):688–98.PubMedCrossRefGoogle Scholar
  6. 6.
    Bianco-Miotto T, Chiam K, Buchanan G, Jindal S, Day TK, Thomas M, et al. Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development. Cancer Epidemiol Biomark Prev. 2010;19(10):2611–22.CrossRefGoogle Scholar
  7. 7.
    Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM, et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 2009;69(9):3802–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Robey RW, Chakraborty AR, Basseville A, Luchenko V, Bahr J, Zhan Z, et al. Histone deacetylase inhibitors: emerging mechanisms of resistance. Mol Pharm. 2011;8(6):2021–31.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell. 2002;108(4):475–87.PubMedCrossRefGoogle Scholar
  10. 10.
    Quina AS, Buschbeck M, Di Croce L. Chromatin structure and epigenetics. Biochem Pharmacol. 2006;72(11):1563–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Marks PA, Xu WS. Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem. 2009;107(4):600–8.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene. 2005;363:15–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5(9):769–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6(1):38–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Gloghini A, Buglio D, Khaskhely NM, Georgakis G, Orlowski RZ, Neelapu SS, et al. Expression of histone deacetylases in lymphoma: implication for the development of selective inhibitors. Br J Haematol. 2009;147(4):515–25.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Marks PA, Dokmanovic M. Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin Investig Drugs. 2005;14(12):1497–511.PubMedCrossRefGoogle Scholar
  18. 18.
    Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G, et al. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2005;102(3):673–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Gabrielli BG, Johnstone RW, Saunders NA. Identifying molecular targets mediating the anticancer activity of histone deacetylase inhibitors: a work in progress. Curr Cancer Drug Targets. 2002;2(4):337–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92(15):1210–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Hitomi T, Matsuzaki Y, Yokota T, Takaoka Y, Sakai T. p15(INK4b) in HDAC inhibitor-induced growth arrest. FEBS Lett. 2003;554(3):347–50.PubMedCrossRefGoogle Scholar
  22. 22.
    Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK. Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther. 2003;2(2):151–63.PubMedGoogle Scholar
  23. 23.
    Zhang XD, Gillespie SK, Borrow JM, Hersey P. The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Mol Cancer Ther. 2004;3(4):425–35.PubMedGoogle Scholar
  24. 24.
    Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A, et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med. 2005;11(1):71–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27(32):5459–68.PubMedCrossRefGoogle Scholar
  26. 26.
    Marks PA. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin Investig Drugs. 2010;19(9):1049–66.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Rosato RR, Almenara JA, Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res. 2003;63(13):3637–45.PubMedGoogle Scholar
  28. 28.
    Liang D, Kong X, Sang N. Effects of histone deacetylase inhibitors on HIF-1. Cell Cycle. 2006;5(21):2430–5.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Heider U, Kaiser M, Sterz J, Zavrski I, Jakob C, Fleissner C, et al. Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma. Eur J Haematol. 2006;76(1):42–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Beckers T, Burkhardt C, Wieland H, Gimmnich P, Ciossek T, Maier T, et al. Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. Int J Cancer. 2007;121(5):1138–48.PubMedCrossRefGoogle Scholar
  31. 31.
    Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol. 2005;45:495–528.PubMedCrossRefGoogle Scholar
  32. 32.
    Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 2007;25(1):84–90.PubMedCrossRefGoogle Scholar
  33. 33.
    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 USA. 2003;100(8):4389–94.PubMedCrossRefGoogle Scholar
  34. 34.
    Ontoria JM, Altamura S, Di Marco A, Ferrigno F, Laufer R, Muraglia E, et al. Identification of novel, selective, and stable inhibitors of class II histone deacetylases. Validation studies of the inhibition of the enzymatic activity of HDAC4 by small molecules as a novel approach for cancer therapy. J Med Chem. 2009;52(21):6782–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Mai A, Massa S, Pezzi R, Simeoni S, Rotili D, Nebbioso A, et al. Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J Med Chem. 2005;48(9):3344–53.PubMedCrossRefGoogle Scholar
  36. 36.
    Duvic M, Vu J. Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Investig Drugs. 2007;16(7):1111–20.PubMedCrossRefGoogle Scholar
  37. 37.
    Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25(21):3109–15.PubMedCrossRefGoogle Scholar
  38. 38.
    Kavanaugh SM, White LA, Kolesar JM. Vorinostat: a novel therapy for the treatment of cutaneous T-cell lymphoma. Am J Health Syst Pharm. 2010;67(10):793–7.PubMedCrossRefGoogle Scholar
  39. 39.
    O’Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol. 2006;24(1):166–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Crump M, Coiffier B, Jacobsen ED, Sun L, Ricker JL, Xie H, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol. 2008;19(5):964–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(9):1198–203.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ogura M, Ando K, Suzuki T, Ishizawa K, Oh SY, Itoh K, et al. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Br J Haematol. 2014;165(6):768–76.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H, et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res. 2002;62(17):4916–21.PubMedGoogle Scholar
  45. 45.
    Bantscheff M, Hopf C, Savitski MM, Dittmann A, Grandi P, Michon AM, et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat Biotechnol. 2011;29(3):255–65.PubMedCrossRefGoogle Scholar
  46. 46.
    Campas-Moya C. Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today (Barc). 2009;45(11):787–95.CrossRefGoogle Scholar
  47. 47.
    Piekarz RL, Robey R, Sandor V, Bakke S, Wilson WH, Dahmoush L, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001;98(9):2865–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Mercurio C, Minucci S, Pelicci PG. Histone deacetylases and epigenetic therapies of hematological malignancies. Pharmacol Res. 2010;62(1):18–34.PubMedCrossRefGoogle Scholar
  49. 49.
    Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410–7.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117(22):5827–34.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Duvic M, Bates SE, Piekarz R, Eisch R, Kim YH, Lerner A, et al. Responses to romidepsin in patients with cutaneous T-cell lymphoma and prior treatment with systemic chemotherapy. Leuk Lymphoma. 2018;59(4):880–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7:11.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Pro B, Horwitz SM, Prince HM, Foss FM, Sokol L, Greenwood M, et al. Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma. Hematol Oncol. 2017;35(4):914–7.PubMedCrossRefGoogle Scholar
  55. 55.
    George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105(4):1768–76.PubMedCrossRefGoogle Scholar
  56. 56.
    Ellis L, Pan Y, Smyth GK, George DJ, McCormack C, Williams-Truax R, et al. Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res. 2008;14(14):4500–10.PubMedCrossRefGoogle Scholar
  57. 57.
    Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T, et al. Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br J Haematol. 2009;147(1):97–101.PubMedCrossRefGoogle Scholar
  58. 58.
    Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2009;2009:507–19.CrossRefGoogle Scholar
  59. 59.
    Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30(18):2197–203.PubMedCrossRefGoogle Scholar
  60. 60.
    Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, et al. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016;128(2):185–94.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Kapoor S. Inhibition of HDAC6-dependent carcinogenesis: emerging, new therapeutic options besides belinostat. Int J Cancer. 2009;124(2):509.PubMedCrossRefGoogle Scholar
  62. 62.
    Qian X, Ara G, Mills E, LaRochelle WJ, Lichenstein HS, Jeffers M. Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer. Int J Cancer. 2008;122(6):1400–10.PubMedCrossRefGoogle Scholar
  63. 63.
    O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008;7(4):759–68.PubMedCrossRefGoogle Scholar
  65. 65.
    Buglio D, Georgakis GV, Hanabuchi S, Arima K, Khaskhely NM, Liu YJ, et al. Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines. Blood. 2008;112(4):1424–33.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Batlevi CL, Crump M, Andreadis C, Rizzieri D, Assouline SE, Fox S, et al. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br J Haematol. 2017;178(3):434–41.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M, Neelapu S, et al. Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2011;12(13):1222–8.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Jona A, Khaskhely N, Buglio D, Shafer JA, Derenzini E, Bollard CM, et al. The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors. Exp Hematol. 2011;39(10):1007–17.. e1PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Batlevi CL, Kasamon Y, Bociek RG, Lee P, Gore L, Copeland A, et al. ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma. Haematologica. 2016;101(8):968–75.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Adimoolam S, Sirisawad M, Chen J, Thiemann P, Ford JM, Buggy JJ. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci USA. 2007;104(49):19482–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Kachhap SK, Rosmus N, Collis SJ, Kortenhorst MS, Wissing MD, Hedayati M, et al. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS One. 2010;5(6):e11208.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Lopez G, Liu J, Ren W, Wei W, Wang S, Lahat G, et al. Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. Clin Cancer Res. 2009;15(10):3472–83.PubMedCrossRefGoogle Scholar
  73. 73.
    Palmieri D, Lockman PR, Thomas FC, Hua E, Herring J, Hargrave E, et al. Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res. 2009;15(19):6148–57.PubMedCrossRefGoogle Scholar
  74. 74.
    Robert T, Vanoli F, Chiolo I, Shubassi G, Bernstein KA, Rothstein R, et al. HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature. 2011;471(7336):74–9.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Zhang Y, Carr T, Dimtchev A, Zaer N, Dritschilo A, Jung M. Attenuated DNA damage repair by trichostatin A through BRCA1 suppression. Radiat Res. 2007;168(1):115–24.PubMedCrossRefGoogle Scholar
  76. 76.
    Chen CS, Wang YC, Yang HC, Huang PH, Kulp SK, Yang CC, et al. Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Res. 2007;67(11):5318–27.PubMedCrossRefGoogle Scholar
  77. 77.
    Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL, et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res. 2005;11(13):4912–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Yaneva M, Li H, Marple T, Hasty P. Non-homologous end joining, but not homologous recombination, enables survival for cells exposed to a histone deacetylase inhibitor. Nucleic Acids Res. 2005;33(16):5320–30.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Lee JH, Choy ML, Ngo L, Foster SS, Marks PA. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci USA. 2010;107(33):14639–44.PubMedCrossRefGoogle Scholar
  80. 80.
    Lee JH, Choy ML, Ngo L, Venta-Perez G, Marks PA. Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2011;108(49):19629–34.PubMedCrossRefGoogle Scholar
  81. 81.
    Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 2000;97(18):10014–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA. 2004;101(5):1241–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Ju R, Muller MT. Histone deacetylase inhibitors activate p21(WAF1) expression via ATM. Cancer Res. 2003;63(11):2891–7.PubMedGoogle Scholar
  84. 84.
    Sandor V, Senderowicz A, Mertins S, Sackett D, Sausville E, Blagosklonny MV, et al. P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer. 2000;83(6):817–25.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Qiu L, Burgess A, Fairlie DP, Leonard H, Parsons PG, Gabrielli BG. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell. 2000;11(6):2069–83.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Garcia-Manero G. Demethylating agents in myeloid malignancies. Curr Opin Oncol. 2008;20(6):705–10.PubMedCrossRefGoogle Scholar
  87. 87.
    Marks PA. Thioredoxin in cancer—role of histone deacetylase inhibitors. Semin Cancer Biol. 2006;16(6):436–43.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Hu Y, Lu W, Chen G, Zhang H, Jia Y, Wei Y, et al. Overcoming resistance to histone deacetylase inhibitors in human leukemia with the redox modulating compound beta-phenylethyl isothiocyanate. Blood. 2010;116(15):2732–41.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Rosato RR, Almenara JA, Maggio SC, Coe S, Atadja P, Dent P, et al. Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther. 2008;7(10):3285–97.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Cerveny L, Svecova L, Anzenbacherova E, Vrzal R, Staud F, Dvorak Z, et al. Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos. 2007;35(7):1032–41.PubMedCrossRefGoogle Scholar
  91. 91.
    Frommel TO, Coon JS, Tsuruo T, Roninson IB. Variable effects of sodium butyrate on the expression and function of the MDR1 (P-glycoprotein) gene in colon carcinoma cell lines. Int J Cancer. 1993;55(2):297–302.PubMedCrossRefGoogle Scholar
  92. 92.
    Kim YK, Kim NH, Hwang JW, Song YJ, Park YS, Seo DW, et al. Histone deacetylase inhibitor apicidin-mediated drug resistance: involvement of P-glycoprotein. Biochem Biophys Res Commun. 2008;368(4):959–64.PubMedCrossRefGoogle Scholar
  93. 93.
    Xiao JJ, Huang Y, Dai Z, Sadee W, Chen J, Liu S, et al. Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,2 0,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 2005;314(1):467–75.PubMedCrossRefGoogle Scholar
  94. 94.
    Yamada H, Arakawa Y, Saito S, Agawa M, Kano Y, Horiguchi-Yamada J. Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile. Leuk Res. 2006;30(6):723–34.PubMedCrossRefGoogle Scholar
  95. 95.
    Lee JS, Paull K, Alvarez M, Hose C, Monks A, Grever M, et al. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 1994;46(4):627–38.PubMedGoogle Scholar
  96. 96.
    Piekarz RL, Robey RW, Zhan Z, Kayastha G, Sayah A, Abdeldaim AH, et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood. 2004;103(12):4636–43.PubMedCrossRefGoogle Scholar
  97. 97.
    Okada T, Tanaka K, Nakatani F, Sakimura R, Matsunobu T, Li X, et al. Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing’s sarcoma cells. Int J Cancer. 2006;118(1):90–7.PubMedCrossRefGoogle Scholar
  98. 98.
    Robey RW, Zhan Z, Piekarz RL, Kayastha GL, Fojo T, Bates SE. Increased MDR1 expression in normal and malignant peripheral blood mononuclear cells obtained from patients receiving depsipeptide (FR901228, FK228, NSC630176). Clin Cancer Res. 2006;12(5):1547–55.PubMedCrossRefGoogle Scholar
  99. 99.
    Peart MJ, Tainton KM, Ruefli AA, Dear AE, Sedelies KA, O’Reilly LA, et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res. 2003;63(15):4460–71.PubMedGoogle Scholar
  100. 100.
    Lindemann RK, Newbold A, Whitecross KF, Cluse LA, Frew AJ, Ellis L, et al. Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. Proc Natl Acad Sci USA. 2007;104(19):8071–6.PubMedCrossRefGoogle Scholar
  101. 101.
    Condorelli F, Gnemmi I, Vallario A, Genazzani AA, Canonico PL. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol. 2008;153(4):657–68.PubMedCrossRefGoogle Scholar
  102. 102.
    Duan H, Heckman CA, Boxer LM. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol. 2005;25(5):1608–19.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Lucas DM, Davis ME, Parthun MR, Mone AP, Kitada S, Cunningham KD, et al. The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia. 2004;18(7):1207–14.PubMedCrossRefGoogle Scholar
  104. 104.
    Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood. 2003;101(10):4055–62.PubMedCrossRefGoogle Scholar
  105. 105.
    Shao W, Growney JD, Feng Y, O’Connor G, Pu M, Zhu W, et al. Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: defining molecular mechanisms of resistance. Int J Cancer. 2010;127(9):2199–208.PubMedCrossRefGoogle Scholar
  106. 106.
    Inoue S, Walewska R, Dyer MJ, Cohen GM. Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells. Leukemia. 2008;22(4):819–25.PubMedCrossRefGoogle Scholar
  107. 107.
    Zhang Y, Adachi M, Kawamura R, Imai K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ. 2006;13(1):129–40.PubMedCrossRefGoogle Scholar
  108. 108.
    Aggarwal BB. Nuclear factor-kappaB: the enemy within. Cancer Cell. 2004;6(3):203–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18(49):6853–66.PubMedCrossRefGoogle Scholar
  110. 110.
    Dai Y, Rahmani M, Dent P, Grant S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol. 2005;25(13):5429–44.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Domingo-Domenech J, Pippa R, Tapia M, Gascon P, Bachs O, Bosch M. Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Treat. 2008;112(1):53–62.PubMedCrossRefGoogle Scholar
  112. 112.
    Rosato RR, Kolla SS, Hock SK, Almenara JA, Patel A, Amin S, et al. Histone deacetylase inhibitors activate NF-kappaB in human leukemia cells through an ATM/NEMO-related pathway. J Biol Chem. 2010;285(13):10064–77.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Rundall BK, Denlinger CE, Jones DR. Combined histone deacetylase and NF-kappaB inhibition sensitizes non-small cell lung cancer to cell death. Surgery. 2004;136(2):416–25.PubMedCrossRefGoogle Scholar
  114. 114.
    Duan J, Friedman J, Nottingham L, Chen Z, Ara G, Van Waes C. Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol Cancer Ther. 2007;6(1):37–50.PubMedCrossRefGoogle Scholar
  115. 115.
    Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97–105.PubMedCrossRefGoogle Scholar
  116. 116.
    Rascle A, Johnston JA, Amati B. Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5. Mol Cell Biol. 2003;23(12):4162–73.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Zhang C, Richon V, Ni X, Talpur R, Duvic M. Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol. 2005;125(5):1045–52.PubMedCrossRefGoogle Scholar
  118. 118.
    Lee JH, Choy ML, Marks PA. Mechanisms of resistance to histone deacetylase inhibitors. Adv Cancer Res. 2012;116:39–86.PubMedCrossRefGoogle Scholar
  119. 119.
    Fantin VR, Loboda A, Paweletz CP, Hendrickson RC, Pierce JW, Roth JA, et al. Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. Cancer Res. 2008;68(10):3785–94.PubMedCrossRefGoogle Scholar
  120. 120.
    Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood. 2009;114(24):5024–33.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1(3):181–93.PubMedCrossRefGoogle Scholar
  122. 122.
    Epping MT, Wang L, Plumb JA, Lieb M, Gronemeyer H, Brown R, et al. A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2007;104(45):17777–82.PubMedCrossRefGoogle Scholar
  123. 123.
    Bazzaro M, Santillan A, Lin Z, Tang T, Lee MK, Bristow RE, et al. Myosin II co-chaperone general cell UNC-45 overexpression is associated with ovarian cancer, rapid proliferation, and motility. Am J Pathol. 2007;171(5):1640–9.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Lopez G, Torres K, Liu J, Hernandez B, Young E, Belousov R, et al. Autophagic survival in resistance to histone deacetylase inhibitors: novel strategies to treat malignant peripheral nerve sheath tumors. Cancer Res. 2011;71(1):185–96.PubMedCrossRefGoogle Scholar
  126. 126.
    Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008;269(1):7–17.PubMedCrossRefGoogle Scholar
  127. 127.
    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–29.PubMedCrossRefGoogle Scholar
  128. 128.
    Lee YT, Miller LD, Gubin AN, Makhlouf F, Wojda U, Barrett AJ, et al. Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays. Blood. 2001;98(6):1914–21.PubMedCrossRefGoogle Scholar
  129. 129.
    Baumeister P, Dong D, Fu Y, Lee AS. Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. Mol Cancer Ther. 2009;8(5):1086–94.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Lee AS. The Par-4-GRP78 TRAIL, more twists and turns. Cancer Biol Ther. 2009;8(22):2103–5.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Shi Y, Gerritsma D, Bowes AJ, Capretta A, Werstuck GH. Induction of GRP78 by valproic acid is dependent upon histone deacetylase inhibition. Bioorg Med Chem Lett. 2007;17(16):4491–4.PubMedCrossRefGoogle Scholar
  132. 132.
    Wang JF, Bown C, Young LT. Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78. Mol Pharmacol. 1999;55(3):521–7.PubMedGoogle Scholar
  133. 133.
    Kahali S, Sarcar B, Fang B, Williams ES, Koomen JM, Tofilon PJ, et al. Activation of the unfolded protein response contributes toward the antitumor activity of vorinostat. Neoplasia. 2010;12(1):80–6.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Rao R, Nalluri S, Kolhe R, Yang Y, Fiskus W, Chen J, et al. Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther. 2010;9(4):942–52.PubMedCrossRefGoogle Scholar
  135. 135.
    Rao R, Nalluri S, Fiskus W, Savoie A, Buckley KM, Ha K, et al. Role of CAAT/enhancer binding protein homologous protein in panobinostat-mediated potentiation of bortezomib-induced lethal endoplasmic reticulum stress in mantle cell lymphoma cells. Clin Cancer Res. 2010;16(19):4742–54.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Ding JRM, Narita T, Masaki A, Mori F, Ito A, Kusumoto S, et al. Reduced expression of HDAC3 contributes to the resistance against HDAC inhibitor, Vorinostat (SAHA) in mature lymphoid malignancies. Blood. 2012;120(21):1342.Google Scholar
  137. 137.
    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.PubMedCrossRefGoogle Scholar
  138. 138.
    Kruh GD. Introduction to resistance to anticancer agents. Oncogene. 2003;22(47):7262–4.PubMedCrossRefGoogle Scholar
  139. 139.
    Dedes KJ, Dedes I, Imesch P, von Bueren AO, Fink D, Fedier A. Acquired vorinostat resistance shows partial cross-resistance to ‘second-generation’ HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities. Anti-Cancer Drugs. 2009;20(5):321–33.PubMedCrossRefGoogle Scholar
  140. 140.
    Fiskus W, Rao R, Fernandez P, Herger B, Yang Y, Chen J, et al. Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells. Blood. 2008;112(7):2896–905.PubMedCrossRefGoogle Scholar
  141. 141.
    Islam SEC, Qu N, Persky D, Carew J, Nawrocki S. Oncolytic reovirus is an effective treatment for histone deacetylase inhibitor resistant T-cell lymphoma. American society of hematology annual meeting oral and poster abstracts 2018.Google Scholar
  142. 142.
    Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141(1):69–80.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Hu B, Younes A, Westin JR, Turturro F, Claret L, Feng L, et al. Phase-I and randomized phase-II trial of panobinostat in combination with ICE (ifosfamide, carboplatin, etoposide) in relapsed or refractory classical Hodgkin lymphoma. Leuk Lymphoma. 2018;59(4):863–70.PubMedCrossRefGoogle Scholar
  144. 144.
    Johnston BCA, Nikolinakos P, Beaven A, Barta S, Bhat G, Song T, et al. Safe and effective treatment of patients with Peripheral T-Cell Lymphoma (PTCL) with the novel HDAC inhibitor, Belinostat, in combination with CHOP: results of the Bel-CHOP phase 1 trial. Blood. 2015;126(23):253.Google Scholar
  145. 145.
    Lu X, Ning Z, Li Z, Cao H, Wang X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis Res. 2016;5(3):185–91.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Shi Y, Dong M, Hong X, Zhang W, Feng J, Zhu J, et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015;26(8):1766–71.PubMedCrossRefGoogle Scholar
  147. 147.
    Oki Y, Buglio D, Fanale M, Fayad L, Copeland A, Romaguera J, et al. Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res. 2013;19(24):6882–90.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Yazbeck V, Shafer D, Perkins EB, Coppola D, Sokol L, Richards KL, et al. A phase II trial of Bortezomib and Vorinostat in mantle cell lymphoma and diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(9):569–75.. e1PubMedCrossRefGoogle Scholar
  149. 149.
    Tan D, Phipps C, Hwang WY, Tan SY, Yeap CH, Chan YH, et al. Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial. Lancet Haematol. 2015;2(8):e326–33.PubMedCrossRefGoogle Scholar
  150. 150.
    Barnes JA, Redd R, Fisher DC, Hochberg EP, Takvorian T, Neuberg D, et al. Panobinostat in combination with rituximab in heavily pretreated diffuse large B-cell lymphoma: results of a phase II study. Hematol Oncol. 2018;36(4):633–7.PubMedCrossRefGoogle Scholar
  151. 151.
    Shah RR. Safety and tolerability of Histone Deacetylase (HDAC) inhibitors in oncology. Drug Saf. 2019;42(2):235–45.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Pediatric Hematology/OncologyNew York Medical CollegeValhallaUSA
  2. 2.The Hospital for Sick Children, Department of PediatricsUniversity of TorontoTorontoCanada

Personalised recommendations