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Targeting Mantle Cell Lymphoma with a Strategy of Combined Proteasome and Histone Deacetylase Inhibition

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

Although approved for over a decade, the clinical utility of proteasome inhibitors (PIs) remains largely restricted to the treatment of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL). This has fueled interest in understanding mechanisms of resistance to their antineoplastic actions, leading to the development of new and improved PIs (e.g., carfilzomib, ixazomib, marizomib) and rational combinations with other novel classes of targeted agents. With respect to the latter, histone deacetylase inhibitors (HDACIs) represent one of the most extensively studied classes of agents. PIs and HDACIs interact at multiple levels to trigger synergistic cell killing in a variety of tumor types through multiple mechanisms, including induction of oxidative stress and DNA damage, PI-mediated inhibition of the cytoprotective NF-κB pathway activated by HDACIs, and promotion of proteotoxic stress through simultaneous proteasome inhibition and disruption of aggresome formation and chaperone proteins, leading to the accumulation of misfolded proteins. Clinically, this combination may be closest to regulatory approval in MM, but represents a promising avenue of investigation in MCL, a relatively uncommon but challenging disease that has been the focus of much recent attention given Food and Drug Administration approvals in 2013 for the immunomodulatory drug lenalidomide and the first-in-class Bruton’s tyrosine kinase inhibitor, ibrutinib. In this chapter, we discuss the mechanisms of action of and interactions between PIs and HDACIs with an MCL focus and review the relevant preclinical and clinical data.

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Abbreviations

ABC:

Activated B-cell

AML:

Acute myeloid leukemia

ATM:

Ataxia telangiectasia mutated

ATR:

ATM and Rad3 related

BCR:

B-cell receptor

BTK:

Bruton’s tyrosine kinase

CDK:

Cyclin-dependent kinases

CDT1:

Chromatin licensing and DNA replication factor-1

c-FLIP:

Cellular FLICE-like inhibitory protein

CHOP:

CAAT-/enhancer-binding protein homologous protein

CTCL:

Cutaneous T-cell lymphoma

DDR:

DNA damage response

DLBCL:

Diffuse large B-cell lymphoma

DNMT1:

DNA methyltransferase 1

DSB:

Double-strand breaks

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

FL:

Follicular lymphoma

FLICE:

FADD-like IL-1β-converting enzyme

GC:

Germinal center

GEP:

Gene expression profiling

GSK3β:

Glycogen synthase kinase-3-beta

HAT:

Histone acetyl transferases

HDAC:

Histone deacetylase

HDACI:

Histone deacetylase inhibitor

HDM4:

Human homolog of MDM4

Hsp90:

Heat shock protein 90

IgVH:

Immunoglobulin heavy chain variable region

IKK:

IκB kinase

IκB:

I kappa B

JAK:

Janus kinase

JNK:

Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MCL:

Mantle cell lymphoma

Mcl-1:

Myeloid cell leukemia 1

MDM2:

Murine double minute homolog 2

MIPI:

Mantle cell lymphoma international prognostic index

MM:

Multiple myeloma

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor kappa B

NHEJ:

Nonhomologous end joining

NHL:

Non-Hodgkin lymphomas

ORR:

Overall response rate

PERK:

Protein kinase RNA-like ER kinase

PI:

Proteasome inhibitor

PRDM1:

PR domain zinc finger protein 1, Blimp1

Rb:

Retinoblastoma protein

R-CHOP:

Rituximab, cyclophosphamide, doxorubicin, vincristine prednisone

ROS:

Reactive oxygen species

STAT:

Signal transducer and activator of transcription

TTP:

Time to progression

UPR:

Unfolded protein response

UPS:

Ubiquitin proteasome system

VEGF:

Vascular endothelial growth factor

XIAP:

X-linked inhibitor of apoptosis

References

  1. Perez-Galan P, Dreyling M, Wiestner A (2011) Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood 117:26–38

    PubMed  CAS  PubMed Central  Google Scholar 

  2. Vose JM (2013) Mantle cell lymphoma: 2013 update on diagnosis, risk-stratification, and clinical management. Am J Hematol 88:1082–1088

    PubMed  CAS  Google Scholar 

  3. Jares P, Colomer D, Campo E (2012) Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 122:3416–3423

    PubMed  CAS  PubMed Central  Google Scholar 

  4. Navarro A, Clot G, Royo C, Jares P, Hadzidimitriou A, Agathangelidis A, Bikos V, Darzentas N, Papadaki T, Salaverria I et al (2012) Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res 72:5307–5316

    PubMed  CAS  PubMed Central  Google Scholar 

  5. Martin P, Chadburn A, Christos P, Weil K, Furman RR, Ruan J, Elstrom R, Niesvizky R, Ely S, Diliberto M et al (2009) Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27:1209–1213

    PubMed  Google Scholar 

  6. Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK et al (2012) Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367:520–531

    PubMed  CAS  Google Scholar 

  7. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C et al (2013) Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203–1210

    PubMed  CAS  Google Scholar 

  8. Kane RC, Dagher R, Farrell A, Ko CW, Sridhara R, Justice R, Pazdur R (2007) Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 13:5291–5294

    PubMed  CAS  Google Scholar 

  9. Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, Zhang L, Cicero S, Fu T, Witzig TE (2013) Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol 31:3688–3695

    PubMed  CAS  Google Scholar 

  10. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME et al (2013) Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507–516

    PubMed  CAS  Google Scholar 

  11. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A et al (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829

    PubMed  CAS  Google Scholar 

  12. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P et al (2012) Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119:4597–4607

    PubMed  CAS  Google Scholar 

  13. Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5:417–421

    PubMed  CAS  Google Scholar 

  14. Beltran E, Fresquet V, Martinez-Useros J, Richter-Larrea JA, Sagardoy A, Sesma I, Almada LL, Montes-Moreno S, Siebert R, Gesk S et al (2011) A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma. Proc Natl Acad Sci U S A 108:12461–12466

    PubMed  CAS  PubMed Central  Google Scholar 

  15. Martinez N, Camacho FI, Algara P, Rodriguez A, Dopazo A, Ruiz-Ballesteros E, Martin P, Martinez-Climent JA, Garcia-Conde J, Menarguez J et al (2003) The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. Cancer Res 63:8226–8232

    PubMed  CAS  Google Scholar 

  16. Pham LV, Tamayo AT, Yoshimura LC, Lo P, Ford RJ (2003) Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 171:88–95

    PubMed  CAS  Google Scholar 

  17. Roue G, Perez-Galan P, Lopez-Guerra M, Villamor N, Campo E, Colomer D (2007) Selective inhibition of IkappaB kinase sensitizes mantle cell lymphoma B cells to TRAIL by decreasing cellular FLIP level. J Immunol 178:1923–1930

    PubMed  CAS  Google Scholar 

  18. Liang M, Han X, Vadhan-Raj S, Nguyen M, Zhang YH, Fernandez M, Drakos E, Konoplev SN, Yin CC, Miranda RN et al (2010) HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis. Mod Pathol 23:381–391

    PubMed  CAS  Google Scholar 

  19. Kurtova AV, Tamayo AT, Ford RJ, Burger JA (2009) Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood 113:4604–4613

    PubMed  CAS  Google Scholar 

  20. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, Anderson KC (1996) Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87:1104–1112

    PubMed  CAS  Google Scholar 

  21. Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A, Yu Y, Remache Y, Weniger MA, Rafiq S et al (2010) Genome wide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 116:1025–1034

    PubMed  CAS  PubMed Central  Google Scholar 

  22. Zhang X, Chen X, Lin J, Lwin T, Wright G, Moscinski LC, Dalton WS, Seto E, Wright K, Sotomayor E et al (2012) Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. Oncogene 31:3002–3008

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Zhang X, Zhao X, Fiskus W, Lin J, Lwin T, Rao R, Zhang Y, Chan JC, Fu K, Marquez VE et al (2012) Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 22: 506–523

    PubMed  CAS  PubMed Central  Google Scholar 

  24. Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349–360

    PubMed  CAS  Google Scholar 

  25. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    PubMed  CAS  Google Scholar 

  26. Bogner C, Ringshausen I, Schneller F, Fend F, Quintanilla-Martinez L, Hacker G, Goetze K, Oostendorp R, Peschel C, Decker T (2003) Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells. Br J Haematol 122:260–268

    PubMed  CAS  Google Scholar 

  27. Bogner C, Schneller F, Hipp S, Ringshausen I, Peschel C, Decker T (2003) Cycling B-CLL cells are highly susceptible to inhibition of the proteasome: involvement of p27, early D-type cyclins, Bax, and caspase-dependent and -independent pathways. Exp Hematol 31:218–225

    PubMed  CAS  Google Scholar 

  28. Drexler HC (1997) Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad Sci U S A 94:855–860

    PubMed  CAS  PubMed Central  Google Scholar 

  29. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076

    PubMed  CAS  Google Scholar 

  30. Masdehors P, Merle-Beral H, Maloum K, Omura S, Magdelenat H, Delic J (2000) Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. Blood 96:269–274

    PubMed  CAS  Google Scholar 

  31. Tan C, Waldmann TA (2002) Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia. Cancer Res 62:1083–1086

    PubMed  CAS  Google Scholar 

  32. Bold RJ, Virudachalam S, McConkey DJ (2001) Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 100:11–17

    PubMed  CAS  Google Scholar 

  33. Frankel A, Man S, Elliott P, Adams J, Kerbel RS (2000) Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 6:3719–3728

    PubMed  CAS  Google Scholar 

  34. Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, Jiang JD, Muggia FM, Perez-Soler R (2002) PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 1: 841–849

    PubMed  CAS  Google Scholar 

  35. Shah SA, Potter MW, McDade TP, Ricciardi R, Perugini RA, Elliott PJ, Adams J, Callery MP (2001) 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 82:110–122

    PubMed  CAS  Google Scholar 

  36. Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E, Adams J, Elliott P, Van Waes C (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7:1419–1428

    PubMed  CAS  Google Scholar 

  37. MacLaren AP, Chapman RS, Wyllie AH, Watson CJ (2001) P53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells. Cell Death Differ 8:210–218

    PubMed  CAS  Google Scholar 

  38. Kudo Y, Takata T, Ogawa I, Kaneda T, Sato S, Takekoshi T, Zhao M, Miyauchi M, Nikai H (2000) p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells. Clin Cancer Res 6:916–923

    PubMed  CAS  Google Scholar 

  39. Drexler HC, Risau W, Konerding MA (2000) Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells. FASEB J 14:65–77

    PubMed  CAS  Google Scholar 

  40. Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ, Jordan CT (2002) Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A 99:16220–16225

    PubMed  CAS  PubMed Central  Google Scholar 

  41. Attar EC, Johnson JL, Amrein PC, Lozanski G, Wadleigh M, DeAngelo DJ, Kolitz JE, Powell BL, Voorhees P, Wang ES et al (2013) Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J Clin Oncol 31:923–929

    PubMed  CAS  PubMed Central  Google Scholar 

  42. An B, Goldfarb RH, Siman R, Dou QP (1998) Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 5:1062–1075

    PubMed  CAS  Google Scholar 

  43. Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Podar K, Munshi NC, Mitsiades N et al (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101:1530–1534

    PubMed  CAS  Google Scholar 

  44. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP et al (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374–14379

    PubMed  CAS  PubMed Central  Google Scholar 

  45. Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Dunner K Jr, Huang P, Abbruzzese JL, McConkey DJ (2005) Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res 65:11658–11666

    PubMed  CAS  Google Scholar 

  46. Yu C, Rahmani M, Dent P, Grant S (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295:555–566

    PubMed  CAS  Google Scholar 

  47. Ling YH, Liebes L, Zou Y, Perez-Soler R (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278:33714–33723

    PubMed  CAS  Google Scholar 

  48. Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D (2006) The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 107:257–264

    PubMed  CAS  Google Scholar 

  49. Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61:3535–3540

    PubMed  CAS  Google Scholar 

  50. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V et al (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277:16639–16647

    PubMed  CAS  Google Scholar 

  51. Jeremias I, Kupatt C, Baumann B, Herr I, Wirth T, Debatin KM (1998) Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells. Blood 91:4624–4631

    PubMed  CAS  Google Scholar 

  52. Orlowski RZ, Small GW, Shi YY (2002) Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. J Biol Chem 277:27864–27871

    PubMed  CAS  Google Scholar 

  53. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107:4907–4916

    PubMed  CAS  PubMed Central  Google Scholar 

  54. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH (2003) Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A 100:9946–9951

    PubMed  CAS  PubMed Central  Google Scholar 

  55. Nawrocki ST, Carew JS, Dunner K Jr, Boise LH, Chiao PJ, Huang P, Abbruzzese JL, McConkey DJ (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 65:11510–11519

    PubMed  CAS  Google Scholar 

  56. Vaziri SA, Hill J, Chikamori K, Grabowski DR, Takigawa N, Chawla-Sarkar M, Rybicki LR, Gudkov AV, Mekhail T, Bukowski RM et al (2005) Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3sigma and survivin. Mol Cancer Ther 4:1880–1890

    PubMed  CAS  Google Scholar 

  57. Luciano F, Jacquel A, Colosetti P, Herrant M, Cagnol S, Pages G, Auberger P (2003) Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 22:6785–6793

    PubMed  CAS  Google Scholar 

  58. Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, Shiraishi N, Ribatti D, Nico B, Vacca A et al (2006) Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 66:184–191

    PubMed  CAS  Google Scholar 

  59. LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J et al (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62: 4996–5000

    PubMed  CAS  Google Scholar 

  60. Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ (2003) Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol Cancer Ther 2:835–843

    PubMed  CAS  Google Scholar 

  61. Zhang HG, Wang J, Yang X, Hsu HC, Mountz JD (2004) Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 23:2009–2015

    PubMed  CAS  Google Scholar 

  62. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, Mitsiades C, Munshi NC, Richardson PG, Carrasco RD et al (2009) Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 114:1046–1052

    PubMed  CAS  PubMed Central  Google Scholar 

  63. Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S (2008) Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer 7:40

    PubMed  PubMed Central  Google Scholar 

  64. Rizzatti EG, Mora-Jensen H, Weniger MA, Gibellini F, Lee E, Daibata M, Lai R, Wiestner A (2008) Noxa mediates bortezomib induced apoptosis in both sensitive and intrinsically resistant mantle cell lymphoma cells and this effect is independent of constitutive activity of the AKT and NF-kappaB pathways. Leuk Lymphoma 49:798–808

    PubMed  CAS  Google Scholar 

  65. Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM et al (2009) Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 113:6069–6076

    PubMed  CAS  PubMed Central  Google Scholar 

  66. Orlowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV (1998) Tumor growth inhibition induced in a murine model of human Burkitt’s lymphoma by a proteasome inhibitor. Cancer Res 58:4342–4348

    PubMed  CAS  Google Scholar 

  67. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM, Walter P (2007) IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944–949

    PubMed  CAS  PubMed Central  Google Scholar 

  68. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622

    PubMed  CAS  Google Scholar 

  69. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617

    PubMed  CAS  Google Scholar 

  70. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498

    PubMed  CAS  Google Scholar 

  71. Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, Wu ZQ, Borad MJ, Frantzen M, Roussos E et al (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144

    PubMed  CAS  Google Scholar 

  72. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380

    PubMed  CAS  Google Scholar 

  73. Ogiso Y, Tomida A, Lei S, Omura S, Tsuruo T (2000) Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. Cancer Res 60:2429–2434

    PubMed  CAS  Google Scholar 

  74. Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J (1999) The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2638–2645

    PubMed  CAS  Google Scholar 

  75. Chandra J, Niemer I, Gilbreath J, Kliche KO, Andreeff M, Freireich EJ, Keating M, McConkey DJ (1998) Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. Blood 92:4220–4229

    PubMed  CAS  Google Scholar 

  76. Russo SM, Tepper JE, Baldwin AS Jr, Liu R, Adams J, Elliott P, Cusack JC Jr (2001) Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Int J Radiat Oncol Biol Phys 50:183–193

    PubMed  CAS  Google Scholar 

  77. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    PubMed  CAS  Google Scholar 

  78. Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274:784–787

    PubMed  CAS  Google Scholar 

  79. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683

    PubMed  CAS  Google Scholar 

  80. Wang CY, Cusack JC Jr, Liu R, Baldwin AS Jr (1999) Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med 5:412–417

    PubMed  Google Scholar 

  81. Desai SD, Li TK, Rodriguez-Bauman A, Rubin EH, Liu LF (2001) Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res 61:5926–5932

    PubMed  CAS  Google Scholar 

  82. Loo TW, Clarke DM (1999) The human multidrug resistance P-glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy. FASEB J 13:1724–1732

    PubMed  CAS  Google Scholar 

  83. Loo TW, Clarke DM (1998) Superfolding of the partially unfolded core-glycosylated intermediate of human P-glycoprotein into the mature enzyme is promoted by substrate-induced transmembrane domain interactions. J Biol Chem 273:14671–14674

    PubMed  CAS  Google Scholar 

  84. Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, Gielen J, Merville MP, Bours V (2003) NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22:90–97

    PubMed  CAS  Google Scholar 

  85. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917

    PubMed  CAS  Google Scholar 

  86. Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N et al (2007) Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25:3892–3901

    PubMed  CAS  Google Scholar 

  87. Kortuem KM, Stewart AK (2013) Carfilzomib. Blood 121:893–897

    PubMed  CAS  Google Scholar 

  88. Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M et al (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 67:1783–1792

    PubMed  CAS  Google Scholar 

  89. Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S et al (2012) An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol 158:739–748

    PubMed  CAS  Google Scholar 

  90. Ruschak AM, Slassi M, Kay LE, Schimmer AD (2011) Novel proteasome inhibitors to overcome bortezomib resistance. J Natl Cancer Inst 103:1007–1017

    PubMed  CAS  Google Scholar 

  91. Chiarle R, Budel LM, Skolnik J, Frizzera G, Chilosi M, Corato A, Pizzolo G, Magidson J, Montagnoli A, Pagano M et al (2000) Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95:619–626

    PubMed  CAS  Google Scholar 

  92. Weniger MA, Rizzatti EG, Perez-Galan P, Liu D, Wang Q, Munson PJ, Raghavachari N, White T, Tweito MM, Dunleavy K et al (2011) Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma. Clin Cancer Res 17:5101–5112

    PubMed  CAS  PubMed Central  Google Scholar 

  93. Derouet M, Thomas L, Cross A, Moots RJ, Edwards SW (2004) Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1. J Biol Chem 279:26915–26921

    PubMed  CAS  Google Scholar 

  94. Nencioni A, Hua F, Dillon CP, Yokoo R, Scheiermann C, Cardone MH, Barbieri E, Rocco I, Garuti A, Wesselborg S et al (2005) Evidence for a protective role of Mcl-1 in proteasome inhibitor-induced apoptosis. Blood 105:3255–3262

    PubMed  CAS  Google Scholar 

  95. Jones RJ, Chen Q, Voorhees PM, Young KH, Bruey-Sedano N, Yang D, Orlowski RZ (2008) Inhibition of the p53 E3 ligase HDM-2 induces apoptosis and DNA damage-independent p53 phosphorylation in mantle cell lymphoma. Clin Cancer Res 14:5416–5425

    PubMed  CAS  PubMed Central  Google Scholar 

  96. Weigert O, Pastore A, Rieken M, Lang N, Hiddemann W, Dreyling M (2007) Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma. Leukemia 21:524–528

    PubMed  CAS  Google Scholar 

  97. Dal Col J, Zancai P, Terrin L, Guidoboni M, Ponzoni M, Pavan A, Spina M, Bergamin S, Rizzo S, Tirelli U et al (2008) Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 111:5142–5151

    PubMed  CAS  Google Scholar 

  98. Hutter G, Zimmermann Y, Rieken M, Hartmann E, Rosenwald A, Hiddemann W, Dreyling M (2012) Proteasome inhibition leads to dephosphorylation and downregulation of protein expression of members of the Akt/mTOR pathway in MCL. Leukemia 26:2442–2444

    PubMed  CAS  Google Scholar 

  99. Shanks JC, Fauble V, Lobocki CA, Terebelo H (2008) Dual proteasome and mTOR inhibition promotes apoptosis in non-Hodgkin lymphoma cell lines. ASH Annual Meeting Abstracts 112:5039

    Google Scholar 

  100. Desai S, Maurin M, Smith MA, Bolick SC, Dessureault S, Tao J, Sotomayor E, Wright KL (2010) PRDM1 is required for mantle cell lymphoma response to bortezomib. Mol Cancer Res 8:907–918

    PubMed  CAS  PubMed Central  Google Scholar 

  101. Baran-Marszak F, Boukhiar M, Harel S, Laguillier C, Roger C, Gressin R, Martin A, Fagard R, Varin-Blank N, Ajchenbaum-Cymbalista F et al (2010) Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma. Haematologica 95:1865–1872

    PubMed  CAS  PubMed Central  Google Scholar 

  102. O’Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E et al (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23:676–684

    PubMed  Google Scholar 

  103. Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L, Dang NH, Samaniego F, Wang M et al (2005) Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23:667–675

    PubMed  CAS  Google Scholar 

  104. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S et al (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867–4874

    PubMed  Google Scholar 

  105. Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S et al (2009) Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol 20:520–525

    PubMed  CAS  Google Scholar 

  106. Belch A, Kouroukis CT, Crump M, Sehn L, Gascoyne RD, Klasa R, Powers J, Wright J, Eisenhauer EA (2007) A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol 18:116–121

    PubMed  CAS  Google Scholar 

  107. O’Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, Orlowski RZ (2009) A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 15:7085–7091

    PubMed  PubMed Central  Google Scholar 

  108. Alsina M, Trudel S, Furman RR, Rosen PJ, O’Connor OA, Comenzo RL, Wong A, Kunkel LA, Molineaux CJ, Goy A (2012) A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res 18:4830–4840

    PubMed  CAS  Google Scholar 

  109. Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J et al (2011) The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 117:2807–2812

    PubMed  CAS  PubMed Central  Google Scholar 

  110. Rosato RR, Grant S (2005) Histone deacetylase inhibitors: insights into mechanisms of lethality. Expert Opin Ther Targets 9:809–824

    PubMed  CAS  Google Scholar 

  111. Grant S, Dai Y (2012) Histone deacetylase inhibitors and rational combination therapies. Adv Cancer Res 116:199–237

    PubMed  CAS  Google Scholar 

  112. Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA, Holloway AJ, Johnstone RW (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102:3697–3702

    PubMed  CAS  PubMed Central  Google Scholar 

  113. Aron JL, Parthun MR, Marcucci G, Kitada S, Mone AP, Davis ME, Shen T, Murphy T, Wickham J, Kanakry C et al (2003) Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood 102:652–658

    PubMed  CAS  Google Scholar 

  114. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X et al (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A 101:540–545

    PubMed  CAS  PubMed Central  Google Scholar 

  115. Rosato RR, Almenara JA, Kolla SS, Maggio SC, Coe S, Gimenez MS, Dent P, Grant S (2007) Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions. Mol Cancer Ther 6:692–702

    PubMed  CAS  Google Scholar 

  116. Rosato RR, Maggio SC, Almenara JA, Payne SG, Atadja P, Spiegel S, Dent P, Grant S (2006) The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. Mol Pharmacol 69:216–225

    PubMed  CAS  Google Scholar 

  117. Sanda T, Okamoto T, Uchida Y, Nakagawa H, Iida S, Kayukawa S, Suzuki T, Oshizawa T, Suzuki T, Miyata N et al (2007) Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells. Leukemia 21:2344–2353

    PubMed  CAS  Google Scholar 

  118. Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG, Keating MJ (2012) Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood 119:1162–1172

    PubMed  CAS  PubMed Central  Google Scholar 

  119. Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q (2005) Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci U S A 102:16090–16095

    PubMed  CAS  PubMed Central  Google Scholar 

  120. Tan J, Zhuang L, Jiang X, Yang KK, Karuturi KM, Yu Q (2006) Apoptosis signal-regulating kinase 1 is a direct target of E2F1 and contributes to histone deacetylase inhibitor-induced apoptosis through positive feedback regulation of E2F1 apoptotic activity. J Biol Chem 281:10508–10515

    PubMed  CAS  Google Scholar 

  121. Chen S, Dai Y, Pei XY, Grant S (2009) Bim upregulation by histone deacetylase inhibitors mediates interactions with the Bcl-2 antagonist ABT-737: evidence for distinct roles for Bcl-2, Bcl-xL, and Mcl-1. Mol Cell Biol 29:6149–6169

    PubMed  CAS  PubMed Central  Google Scholar 

  122. Dai Y, Chen S, Kramer LB, Funk VL, Dent P, Grant S (2008) Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res 14:549–558

    PubMed  CAS  Google Scholar 

  123. Dai Y, Chen S, Wang L, Pei XY, Kramer LB, Dent P, Grant S (2011) Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-kappaB and Bim. Br J Haematol 153:222–235

    PubMed  CAS  PubMed Central  Google Scholar 

  124. Inoue S, Riley J, Gant TW, Dyer MJ, Cohen GM (2007) Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia 21:1773–1782

    PubMed  CAS  Google Scholar 

  125. Terui T, Murakami K, Takimoto R, Takahashi M, Takada K, Murakami T, Minami S, Matsunaga T, Takayama T, Kato J et al (2003) Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors. Cancer Res 63:8948–8954

    PubMed  CAS  Google Scholar 

  126. Xargay-Torrent S, Lopez-Guerra M, Saborit-Villarroya I, Rosich L, Campo E, Roue G, Colomer D (2011) Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters. Clin Cancer Res 17:3956–3968

    PubMed  CAS  Google Scholar 

  127. Glick RD, Swendeman SL, Coffey DC, Rifkind RA, Marks PA, Richon VM, La Quaglia MP (1999) Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma. Cancer Res 59:4392–4399

    PubMed  CAS  Google Scholar 

  128. 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 11:71–76

    PubMed  CAS  Google Scholar 

  129. Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P, Alvarez R, Schiavone EM, Ferrara F, Bresciani F et al (2005) Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 11:77–84

    PubMed  CAS  Google Scholar 

  130. Lindemann RK, Newbold A, Whitecross KF, Cluse LA, Frew AJ, Ellis L, Williams S, Wiegmans AP, Dear AE, Scott CL et al (2007) Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. Proc Natl Acad Sci U S A 104:8071–8076

    PubMed  CAS  PubMed Central  Google Scholar 

  131. Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, Schlossman R, Chauhan D, Munshi NC, Hideshima T et al (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101:4055–4062

    PubMed  CAS  Google Scholar 

  132. Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, Smyth MJ, Johnstone RW (2001) The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci U S A 98:10833–10838

    PubMed  CAS  PubMed Central  Google Scholar 

  133. Li H, Wu X (2004) Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells. Biochem Biophys Res Commun 324:860–867

    PubMed  CAS  Google Scholar 

  134. Nawrocki ST, Carew JS, Douglas L, Cleveland JL, Humphreys R, Houghton JA (2007) Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. Cancer Res 67:6987–6994

    PubMed  CAS  Google Scholar 

  135. Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 97:10014–10019

    PubMed  CAS  PubMed Central  Google Scholar 

  136. Wang H, Zhou W, Zheng Z, Zhang P, Tu B, He Q, Zhu WG (2012) The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair (Amst) 11:146–156

    CAS  Google Scholar 

  137. Rosato RR, Almenara JA, Grant S (2003) 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 63:3637–3645

    PubMed  CAS  Google Scholar 

  138. Dai Y, Rahmani M, Dent P, Grant S (2005) 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 25:5429–5444

    PubMed  CAS  PubMed Central  Google Scholar 

  139. Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G, Ngo L, Holmgren A, Jiang X, Marks PA (2005) Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci U S A 102:673–678

    PubMed  CAS  PubMed Central  Google Scholar 

  140. Xu W, Ngo L, Perez G, Dokmanovic M, Marks PA (2006) Intrinsic apoptotic and thioredoxin pathways in human prostate cancer cell response to histone deacetylase inhibitor. Proc Natl Acad Sci U S A 103:15540–15545

    PubMed  CAS  PubMed Central  Google Scholar 

  141. Petruccelli LA, Dupere-Richer D, Pettersson F, Retrouvey H, Skoulikas S, Miller WH Jr (2011) Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells. PLoS One 6:e20987

    PubMed  CAS  PubMed Central  Google Scholar 

  142. Rosato RR, Almenara JA, Maggio SC, Coe S, Atadja P, Dent P, Grant S (2008) Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther 7:3285–3297

    PubMed  CAS  PubMed Central  Google Scholar 

  143. Rosato RR, Kolla SS, Hock SK, Almenara JA, Patel A, Amin S, Atadja P, Fisher PB, Dent P, Grant S (2010) Histone deacetylase inhibitors activate NF-kappaB in human leukemia cells through an ATM/NEMO-related pathway. J Biol Chem 285:10064–10077

    PubMed  CAS  PubMed Central  Google Scholar 

  144. Gaymes TJ, Padua RA, Pla M, Orr S, Omidvar N, Chomienne C, Mufti GJ, Rassool FV (2006) Histone deacetylase inhibitors (HDI) cause DNA damage in leukemia cells: a mechanism for leukemia-specific HDI-dependent apoptosis? Mol Cancer Res 4:563–573

    PubMed  CAS  Google Scholar 

  145. Hu Y, Lu W, Chen G, Zhang H, Jia Y, Wei Y, Yang H, Zhang W, Fiskus W, Bhalla K et al (2010) Overcoming resistance to histone deacetylase inhibitors in human leukemia with the redox modulating compound beta-phenylethyl isothiocyanate. Blood 116:2732–2741

    PubMed  CAS  PubMed Central  Google Scholar 

  146. Dasmahapatra G, Lembersky D, Kramer L, Fisher RI, Friedberg J, Dent P, Grant S (2010) The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood 115:4478–4487

    PubMed  CAS  PubMed Central  Google Scholar 

  147. Dasmahapatra G, Lembersky D, Son MP, Attkisson E, Dent P, Fisher RI, Friedberg JW, Grant S (2011) Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo. Mol Cancer Ther 10:1686–1697

    PubMed  CAS  PubMed Central  Google Scholar 

  148. Yu X, Guo ZS, Marcu MG, Neckers L, Nguyen DM, Chen GA, Schrump DS (2002) Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 94:504–513

    PubMed  CAS  Google Scholar 

  149. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P et al (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 280:26729–26734

    PubMed  CAS  Google Scholar 

  150. Nimmanapalli R, Fuino L, Bali P, Gasparetto M, Glozak M, Tao J, Moscinski L, Smith C, Wu J, Jove R et al (2003) Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res 63: 5126–5135

    PubMed  CAS  Google Scholar 

  151. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA (2004) Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 13:627–638

    PubMed  CAS  Google Scholar 

  152. 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 102:4842–4847

    PubMed  CAS  PubMed Central  Google Scholar 

  153. 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 U S A 107:14639–14644

    PubMed  CAS  PubMed Central  Google Scholar 

  154. Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, Hiebert SW (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell 30:61–72

    PubMed  CAS  PubMed Central  Google Scholar 

  155. Kachhap SK, Rosmus N, Collis SJ, Kortenhorst MS, Wissing MD, Hedayati M, Shabbeer S, Mendonca J, Deangelis J, Marchionni L et al (2010) Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS One 5:e11208

    PubMed  PubMed Central  Google Scholar 

  156. Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S, Jackson SP (2010) Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol 17:1144–1151

    PubMed  CAS  PubMed Central  Google Scholar 

  157. Robert T, Vanoli F, Chiolo I, Shubassi G, Bernstein KA, Rothstein R, Botrugno OA, Parazzoli D, Oldani A, Minucci S et al (2011) HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature 471:74–79

    PubMed  CAS  PubMed Central  Google Scholar 

  158. Shubassi G, Robert T, Vanoli F, Minucci S, Foiani M (2012) Acetylation: a novel link between double-strand break repair and autophagy. Cancer Res 72:1332–1335

    PubMed  CAS  Google Scholar 

  159. Cerchietti LC, Hatzi K, Caldas-Lopes E, Yang SN, Figueroa ME, Morin RD, Hirst M, Mendez L, Shaknovich R, Cole PA et al (2010) BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. J Clin Invest. doi:10.1172/JCI42869

    PubMed  PubMed Central  Google Scholar 

  160. Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ, Zheng S, Yenamandra A, Locke K, Yuan JL, Bonine-Summers AR et al (2010) Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18:436–447

    PubMed  CAS  PubMed Central  Google Scholar 

  161. 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 115:727–738

    PubMed  CAS  Google Scholar 

  162. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC (2005) Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 102:8567–8572

    PubMed  CAS  PubMed Central  Google Scholar 

  163. Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Andtbacka RH, Dunner K Jr, Pal A, Bornmann WG, Chiao PJ, Huang P et al (2006) Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 66: 3773–3781

    PubMed  CAS  Google Scholar 

  164. Rao R, Nalluri S, Fiskus W, Savoie A, Buckley KM, Ha K, Balusu R, Joshi A, Coothankandaswamy V, Tao J et al (2010) 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 16:4742–4754

    PubMed  CAS  PubMed Central  Google Scholar 

  165. Rao R, Nalluri S, Kolhe R, Yang Y, Fiskus W, Chen J, Ha K, Buckley KM, Balusu R, Coothankandaswamy V et al (2010) Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther 9:942–952

    PubMed  CAS  Google Scholar 

  166. Kahali S, Sarcar B, Prabhu A, Seto E, Chinnaiyan P (2012) Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response. FASEB J 26:2437–2445

    PubMed  CAS  Google Scholar 

  167. Warrener R, Beamish H, Burgess A, Waterhouse NJ, Giles N, Fairlie D, Gabrielli B (2003) Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. FASEB J 17:1550–1552

    PubMed  CAS  Google Scholar 

  168. Stevens FE, Beamish H, Warrener R, Gabrielli B (2008) Histone deacetylase inhibitors induce mitotic slippage. Oncogene 27:1345–1354

    PubMed  CAS  Google Scholar 

  169. Magnaghi-Jaulin L, Eot-Houllier G, Fulcrand G, Jaulin C (2007) Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint. Cancer Res 67:6360–6367

    PubMed  CAS  Google Scholar 

  170. Ishii S, Kurasawa Y, Wong J, Yu-Lee LY (2008) Histone deacetylase 3 localizes to the mitotic spindle and is required for kinetochore-microtubule attachment. Proc Natl Acad Sci U S A 105:4179–4184

    PubMed  CAS  PubMed Central  Google Scholar 

  171. Vrana JA, Decker RH, Johnson CR, Wang Z, Jarvis WD, Richon VM, Ehinger M, Fisher PB, Grant S (1999) Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. Oncogene 18:7016–7025

    PubMed  CAS  Google Scholar 

  172. Dai Y, Guzman ML, Chen S, Wang L, Yeung SK, Pei XY, Dent P, Jordan CT, Grant S (2010) The NF (Nuclear factor)-kappaB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol 151:70–83

    PubMed  CAS  PubMed Central  Google Scholar 

  173. Rascle A, Johnston JA, Amati B (2003) Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5. Mol Cell Biol 23:4162–4173

    PubMed  CAS  PubMed Central  Google Scholar 

  174. Nguyen T, Dai Y, Attkisson E, Kramer L, Jordan N, Nguyen N, Kolluri N, Muschen M, Grant S (2011) HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL + leukemia cells in vitro and in vivo. Clin Cancer Res 17:3219–3232

    PubMed  CAS  PubMed Central  Google Scholar 

  175. Shao W, Growney JD, Feng Y, O’Connor G, Pu M, Zhu W, Yao YM, Kwon P, Fawell S, Atadja P (2010) Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: Defining molecular mechanisms of resistance. Int J Cancer 127:2199–2208

    PubMed  CAS  Google Scholar 

  176. Fotheringham S, Epping MT, Stimson L, Khan O, Wood V, Pezzella F, Bernards R, La Thangue NB (2009) Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 15:57–66

    PubMed  CAS  Google Scholar 

  177. Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV et al (2002) Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21:427–436

    PubMed  CAS  Google Scholar 

  178. Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L, Atadja P, Pili R (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64:6626–6634

    PubMed  CAS  Google Scholar 

  179. Maggio SC, Rosato RR, Kramer LB, Dai Y, Rahmani M, Paik DS, Czarnik AC, Payne SG, Spiegel S, Grant S (2004) The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. Cancer Res 64:2590–2600

    PubMed  CAS  Google Scholar 

  180. Yi C, Ma M, Ran L, Zheng J, Tong J, Zhu J, Ma C, Sun Y, Zhang S, Feng W et al (2012) Function and molecular mechanism of acetylation in autophagy regulation. Science 336: 474–477

    PubMed  CAS  Google Scholar 

  181. Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L, Houghton JA, Huang P, Giles FJ, Cleveland JL (2007) Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 110:313–322

    PubMed  CAS  PubMed Central  Google Scholar 

  182. Gammoh N, Lam D, Puente C, Ganley I, Marks PA, Jiang X (2012) Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci U S A 109:6561–6565

    PubMed  CAS  PubMed Central  Google Scholar 

  183. Almenara J, Rosato R, Grant S (2002) Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 16:1331–1343

    PubMed  CAS  Google Scholar 

  184. Watanabe T (2010) Investigational histone deacetylase inhibitors for non-Hodgkin lymphomas. Expert Opin Investig Drugs 19:1113–1127

    PubMed  CAS  Google Scholar 

  185. Kawamata N, Chen J, Koeffler HP (2007) Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells. Blood 110:2667–2673

    PubMed  CAS  PubMed Central  Google Scholar 

  186. Heider U, Kaiser M, Sterz J, Zavrski I, Jakob C, Fleissner C, Eucker J, Possinger K, Sezer O (2006) Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma. Eur J Haematol 76:42–50

    PubMed  CAS  Google Scholar 

  187. Lwin T, Zhao X, Cheng F, Zhang X, Huang A, Shah B, Zhang Y, Moscinski LC, Choi YS, Kozikowski AP et al (2013) A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J Clin Invest 123:4612–26

    PubMed  CAS  PubMed Central  Google Scholar 

  188. Watanabe T, Kato H, Kobayashi Y, Yamasaki S, Morita-Hoshi Y, Yokoyama H, Morishima Y, Ricker JL, Otsuki T, Miyagi-Maesima A et al (2010) Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Cancer Sci 101:196–200

    PubMed  CAS  Google Scholar 

  189. Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, Matsuoka D, Pulone B, Rotter AJ, Espinoza-Delgado I et al (2011) Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 29:1198–1203

    PubMed  CAS  PubMed Central  Google Scholar 

  190. Wright JJ (2010) Combination therapy of bortezomib with novel targeted agents: an emerging treatment strategy. Clin Cancer Res 16:4094–4104

    PubMed  CAS  Google Scholar 

  191. Mayo MW, Denlinger CE, Broad RM, Yeung F, Reilly ET, Shi Y, Jones DR (2003) Ineffectiveness of histone deacetylase inhibitors to induce apoptosis involves the transcriptional activation of NF-kappa B through the Akt pathway. J Biol Chem 278:18980–18989

    PubMed  CAS  Google Scholar 

  192. Roychowdhury S, Baiocchi RA, Vourganti S, Bhatt D, Blaser BW, Freud AG, Chou J, Chen CS, Xiao JJ, Parthun M et al (2004) Selective efficacy of depsipeptide in a xenograft model of Epstein-Barr virus-positive lymphoproliferative disorder. J Natl Cancer Inst 96:1447–1457

    PubMed  CAS  Google Scholar 

  193. Dai Y, Chen S, Wang L, Pei XY, Funk VL, Kramer LB, Dent P, Grant S (2011) Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. J Biol Chem 286:34036–34050

    PubMed  CAS  PubMed Central  Google Scholar 

  194. Dai Y, Rahmani M, Grant S (2003) An intact NF-kappaB pathway is required for histone deacetylase inhibitor-induced G1 arrest and maturation in U937 human myeloid leukemia cells. Cell Cycle 2:467–472

    PubMed  CAS  Google Scholar 

  195. Pei XY, Dai Y, Grant S (2004) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10:3839–3852

    PubMed  CAS  Google Scholar 

  196. Campbell RA, Sanchez E, Steinberg J, Shalitin D, Li ZW, Chen H, Berenson JR (2010) Vorinostat enhances the antimyeloma effects of melphalan and bortezomib. Eur J Haematol 84:201–211

    PubMed  CAS  Google Scholar 

  197. Heider U, von Metzler I, Kaiser M, Rosche M, Sterz J, Rotzer S, Rademacher J, Jakob C, Fleissner C, Kuckelkorn U et al (2008) Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol 80:133–142

    PubMed  CAS  Google Scholar 

  198. Paoluzzi L, Scotto L, Marchi E, Zain J, Seshan VE, O’Connor OA (2010) Romidepsin and belinostat synergize the antineoplastic effect of bortezomib in mantle cell lymphoma. Clin Cancer Res 16:554–565

    PubMed  CAS  Google Scholar 

  199. Heider U, Rademacher J, Lamottke B, Mieth M, Moebs M, von Metzler I, Assaf C, Sezer O (2009) Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in cutaneous T cell lymphoma. Eur J Haematol 82:440–449

    PubMed  CAS  Google Scholar 

  200. Zhang QL, Wang L, Zhang YW, Jiang XX, Yang F, Wu WL, Janin A, Chen Z, Shen ZX, Chen SJ et al (2009) The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. Leukemia 23:1507–1514

    PubMed  CAS  Google Scholar 

  201. Miller CP, Ban K, Dujka ME, McConkey DJ, Munsell M, Palladino M, Chandra J (2007) NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110:267–277

    PubMed  CAS  PubMed Central  Google Scholar 

  202. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl + cells sensitive and resistant to STI571. Blood 102:3765–3774

    PubMed  CAS  Google Scholar 

  203. Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I et al (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15:5250–5257

    PubMed  CAS  PubMed Central  Google Scholar 

  204. Holkova B, Bose P, Tombes MB, Shrader E, Wan W, Weir-Wiggins C, Stoddert E, Sankala H, Kmieciak M, Roberts JD et al (2012) Phase I trial of belinostat and bortezomib in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia in blast crisis—one year update. ASH Annual Meeting Abstracts 120:3588

    Google Scholar 

  205. Holkova B, Perkins EB, Sokol L, Richards KL, Parekh S, Elstrom R, Badros AZ, Espinoza-Delgado I, Schell MJ, Kimball A et al (2011) A phase II trial of bortezomib and vorinostat in mantle cell lymphoma and diffuse large B-cell lymphoma. ASH Annual Meeting Abstracts 118:779

    Google Scholar 

  206. Holkova B, Shea TC, Bose P, Tombes MB, Shrader E, Wan W, Weir-Wiggins C, Stoddert E, Sankala H, Kmieciak M et al (2012) Phase I study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, or peripheral T-cell lymphoma. ASH Annual Meeting Abstracts 120:1794

    Google Scholar 

  207. Holkova B, Kmieciak M, Bose P, Barr PM, Tombes MB, Shrader E, Cebula E, Pierce E, Herr MM, Sankala H, Feng C et al (2013) Phase I trial of carfilzomib in combination with vorinostat (SAHA) in patients with relapsed/refractory B-cell lymphomas. Blood 122:4375

    Google Scholar 

  208. Hideshima T, Richardson PG, Anderson KC (2011) Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 10:2034–2042

    PubMed  CAS  Google Scholar 

  209. Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan D, Munshi NC et al (2006) Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 108:3441–3449

    PubMed  CAS  PubMed Central  Google Scholar 

  210. Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS et al (2013) PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 122:2331–2337

    PubMed  CAS  Google Scholar 

  211. Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, Jarpe M, van Duzer JH, Mazitschek R, Ogier WC et al (2012) Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119:2579–2589

    PubMed  CAS  PubMed Central  Google Scholar 

  212. Nishioka C, Ikezoe T, Yang J, Takeuchi S, Koeffler HP, Yokoyama A (2008) MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk Res 32:1382–1392

    PubMed  CAS  Google Scholar 

  213. Davenport EL, Moore HE, Dunlop AS, Sharp SY, Workman P, Morgan GJ, Davies FE (2007) Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. Blood 110:2641–2649

    PubMed  CAS  Google Scholar 

  214. Roue G, Perez-Galan P, Mozos A, Lopez-Guerra M, Xargay-Torrent S, Rosich L, Saborit-Villarroya I, Normant E, Campo E, Colomer D (2011) The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78. Blood 117:1270–1279

    PubMed  CAS  Google Scholar 

  215. Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T, Anderson KC (2003) Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 63:6174–6177

    PubMed  CAS  Google Scholar 

  216. Liu S, Liu Z, Xie Z, Pang J, Yu J, Lehmann E, Huynh L, Vukosavljevic T, Takeki M, Klisovic RB et al (2008) Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood 111:2364–2373

    PubMed  CAS  PubMed Central  Google Scholar 

  217. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11:726–734

    PubMed  CAS  PubMed Central  Google Scholar 

  218. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692

    PubMed  CAS  PubMed Central  Google Scholar 

  219. Emanuele S, Lauricella M, Carlisi D, Vassallo B, D’Anneo A, Di Fazio P, Vento R, Tesoriere G (2007) SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis 12:1327–1338

    PubMed  CAS  Google Scholar 

  220. Kikuchi J, Wada T, Shimizu R, Izumi T, Akutsu M, Mitsunaga K, Noborio-Hatano K, Nobuyoshi M, Ozawa K, Kano Y et al (2010) Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma. Blood 116:406–417

    PubMed  CAS  Google Scholar 

  221. Catley L, Weisberg E, Tai YT, Atadja P, Remiszewski S, Hideshima T, Mitsiades N, Shringarpure R, LeBlanc R, Chauhan D et al (2003) NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 102:2615–2622

    PubMed  CAS  Google Scholar 

  222. Bhalla S, Balasubramanian S, David K, Sirisawad M, Buggy J, Mauro L, Prachand S, Miller R, Gordon LI, Evens AM (2009) PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells. Clin Cancer Res 15:3354–3365

    PubMed  CAS  PubMed Central  Google Scholar 

  223. Paoluzzi L, Scotto L, Marchi E, Seshan VE, O’Connor OA (2009) The anti-histaminic cyproheptadine synergizes the antineoplastic activity of bortezomib in mantle cell lymphoma through its effects as a histone deacetylase inhibitor. Br J Haematol 146:656–659

    PubMed  CAS  Google Scholar 

  224. Dai Y, Rahmani M, Grant S (2003) Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 22:7108–7122

    PubMed  CAS  Google Scholar 

  225. Kapanen A, Tucker C, Chikh G, Bally M, Klasa R (2005) Cell based assays completed with the mantle cell lymphoma cell lines Z138 and NCEB-1 indicate that combinations of bortezomid and flavopiridol interact to achieve synergistic activity. ASH Annual Meeting Abstracts 106:2410

    Google Scholar 

  226. Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D et al (2011) Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res 17:3388–3397

    PubMed  CAS  PubMed Central  Google Scholar 

  227. Holkova B, Perkins EB, Bose P, Sullivan DM, Baz R, Tombes MB, Shrader E, Ramakrishnan V, Wan W, Sankala H et al (2012) Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms—update of the “bolus” infusion schedule of alvocidib. ASH Annual Meeting Abstracts 120:2959

    Google Scholar 

  228. Holkova B, Supko JG, Ames MM, Reid JM, Shapiro GI, Perkins EB, Ramakrishnan V, Tombes MB, Honeycutt C, McGovern RM et al (2013) A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Clin Cancer Res 19:1873–1883

    PubMed  CAS  PubMed Central  Google Scholar 

  229. Axelrod M, Ou Z, Brett LK, Zhang L, Lopez ER, Tamayo AT, Gordon V, Ford RJ, Williams ME, Pham LV et al (2014) Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia 28:407–410

    PubMed  CAS  PubMed Central  Google Scholar 

  230. Dasmahapatra G, Patel H, Dent P, Fisher RI, Friedberg J, Grant S (2013) The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol 161:43–56

    PubMed  CAS  PubMed Central  Google Scholar 

  231. Paoluzzi L, Gonen M, Bhagat G, Furman RR, Gardner JR, Scotto L, Gueorguiev VD, Heaney ML, Manova K, O’Connor OA (2008) The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 112:2906–2916

    PubMed  CAS  Google Scholar 

  232. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D (2007) The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 109:4441–4449

    PubMed  CAS  Google Scholar 

  233. Goy A, Ford P, Feldman T, Pecora A, Goldberg S, Donato M, Siegel D, Panush D, Berger MS (2007) A phase 1 trial of the Pan Bcl-2 family inhibitor obatoclax mesylate (GX15-070) in combination with bortezomib in patients with relapsed/refractory mantle cell lymphoma. ASH Annual Meeting Abstracts 110:2569

    Google Scholar 

  234. Wilson WH, O’Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, Tulpule A, Dunleavy K, Xiong H, Chiu YL et al (2010) Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11:1149–1159

    PubMed  CAS  PubMed Central  Google Scholar 

  235. Whitecross KF, Alsop AE, Cluse LA, Wiegmans A, Banks KM, Coomans C, Peart MJ, Newbold A, Lindemann RK, Johnstone RW (2009) Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors. Blood 113:1982–1991

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the following awards to Dr. Grant: R01 CA167708-01A1 and R01 CA100866-09 from the National Institutes of Health, an award from the Leukemia and Lymphoma Society, and an award from Onyx Pharmaceuticals, Inc.

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    Authors and Affiliations

    1. Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

      Michael Batalo, Prithviraj Bose, Beata Holkova & Steven Grant M.D.

    2. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

      Prithviraj Bose, Beata Holkova & Steven Grant M.D.

    3. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA

      Steven Grant M.D.

    4. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA

      Steven Grant M.D.

    5. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA

      Steven Grant M.D.

    6. Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA

      Steven Grant M.D.

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    1. Michael Batalo
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    1. Wayne State University, Detroit, Michigan, USA

      Q. Ping Dou

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    Batalo, M., Bose, P., Holkova, B., Grant, S. (2014). Targeting Mantle Cell Lymphoma with a Strategy of Combined Proteasome and Histone Deacetylase Inhibition. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_6

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