Annals of Hematology

, Volume 90, Issue 8, pp 917–931 | Cite as

Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells

  • Ai-Hua Wang
  • Lin Wei
  • Li Chen
  • Shu-Qing Zhao
  • Wei-Li Wu
  • Zhi-Xiang Shen
  • Jun-Min Li
Original Article


The synergistic effect of proteasome inhibitor bortezomib and valproic acid (VPA), a histone deacetylase inhibitor, were investigated in this study. Co-treatment with VPA and bortezomib on acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cell lines resulted in marked inhibition of proliferation and induction of apoptosis, including a striking increase in mitochondrial injury, caspase cascade activation, and altered expression of Bcl-2 family proteins. Moreover, combination treatment inhibited cyto-protective signaling pathways, including inactivation of nuclear factor κB (NF-κB), the extracellular signal-related kinase (ERK) and Akt pathways, and activated stress-related signaling pathway, including the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) pathways. In addition, this regimen significantly caused G2/M phase arrest, while downregulating the expression of phospho-CDC2 and CyclinD1 as well as increasing p21cip1. Furthermore, combination treatment efficiently induced apoptosis in primary AML/MDS cells, with little effect on normal cells. In summary, these findings indicate that combination treatment with VPA and bortezomib may be a potent therapy for AML/MDS malignancies.


Bortezomib Valproic acid Acute myeloid leukemia Myelodysplastic syndrome 


  1. 1.
    Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479PubMedCrossRefGoogle Scholar
  2. 2.
    Muratani M, Tansey WP (2003) How the ubiquitin–proteasome system controls transcription. Nat Rev Mol Cell Biol 4:192–201PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson KC (2009) Proteasome inhibitors in multiple myeloma. Semin Oncol 36:S20–S26PubMedCrossRefGoogle Scholar
  4. 4.
    Adams J, Palombella VJ, Elliott PJ (2000) Proteasome inhibition: a new strategy in cancer treatment. Invest New Drugs 18:109–121PubMedCrossRefGoogle Scholar
  5. 5.
    Roccaro AM, Hideshima T, Richardson PG, Russo D, Ribatti D, Vacca A, Dammacco F, Anderson KC (2006) Bortezomib as an antitumor agent. Curr Pharm Biotechnol 7:441–448PubMedCrossRefGoogle Scholar
  6. 6.
    Adams J (2002) Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. Curr Opin Chem Biol 6:493–500PubMedCrossRefGoogle Scholar
  7. 7.
    LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62:4996–5000PubMedGoogle Scholar
  8. 8.
    Gatto S, Scappini B, Pham L, Onida F, Milella M, Ball G, Ricci C, Divoky V, Verstovsek S, Kantarjian HM, Keating MJ, Cortes-Franco JE, Beran M (2003) The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate. Haematologica 88:853–863PubMedGoogle Scholar
  9. 9.
    Kelley TW, Alkan S, Srkalovic G, Hsi ED (2004) Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis. Leuk Res 28:845–850PubMedCrossRefGoogle Scholar
  10. 10.
    Zheng B, Georgakis GV, Li Y, Bharti A, McConkey D, Aggarwal BB, Younes A (2004) Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors. Clin Cancer Res 10:3207–3215PubMedCrossRefGoogle Scholar
  11. 11.
    Colado E, Alvarez-Fernandez S, Maiso P, Martin-Sanchez J, Vidriales MB, Garayoa M, Ocio EM, Montero JC, Pandiella A, San Miguel JF (2008) The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype. Haematologica 93:57–66PubMedCrossRefGoogle Scholar
  12. 12.
    Stapnes C, Doskeland AP, Hatfield K, Ersvaer E, Ryningen A, Lorens JB, Gjertsen BT, Bruserud O (2007) The proteasome inhibitors bortezomib and PR-171 have antiproliferative and proapoptotic effects on primary human acute myeloid leukaemia cells. Br J Haematol 136:814–828PubMedCrossRefGoogle Scholar
  13. 13.
    Terpos E, Verrou E, Banti A, Kaloutsi V, Lazaridou A, Zervas K (2007) Bortezomib is an effective agent for MDS/MPD syndrome with 5q-anomaly and thrombocytosis. Leuk Res 31:559–562PubMedCrossRefGoogle Scholar
  14. 14.
    Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G, Schlossman R, Chauhan D, Munshi NC, Hideshima T, Richon VM, Marks PA, Anderson KC (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101:4055–4062PubMedCrossRefGoogle Scholar
  15. 15.
    He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP Jr, Rifkind RA, Marks PA, Richon VM, Pandolfi PP (2001) Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 108:1321–1330PubMedGoogle Scholar
  16. 16.
    Marks PA, Richon VM, Breslow R, Rifkind RA (2001) Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol 13:477–483PubMedCrossRefGoogle Scholar
  17. 17.
    Gridelli C, Rossi A, Maione P (2008) The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer. Crit Rev Oncol Hematol 68:29–36PubMedCrossRefGoogle Scholar
  18. 18.
    Yin L, Laevsky G, Giardina C (2001) Butyrate suppression of colonocyte NF-kappa B activation and cellular proteasome activity. J Biol Chem 276:44641–44646PubMedCrossRefGoogle Scholar
  19. 19.
    Heider U, von Metzler I, Kaiser M, Rosche M, Sterz J, Rotzer S, Rademacher J, Jakob C, Fleissner C, Kuckelkorn U, Kloetzel PM, Sezer O (2008) Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol 80:133–142PubMedCrossRefGoogle Scholar
  20. 20.
    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 10:3839–3852PubMedCrossRefGoogle Scholar
  21. 21.
    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 102:3765–3774PubMedCrossRefGoogle Scholar
  22. 22.
    Zhang QL, Wang L, Zhang YW, Jiang XX, Yang F, Wu WL, Janin A, Chen Z, Shen ZX, Chen SJ, Zhao WL (2009) The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. Leukemia 23:1507–1514PubMedCrossRefGoogle Scholar
  23. 23.
    Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I, Baer MR, Holleran JL, Egorin MJ, Grant S (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15:5250–5257PubMedCrossRefGoogle Scholar
  24. 24.
    Kawagoe R, Kawagoe H, Sano K (2002) Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res 26:495–502PubMedCrossRefGoogle Scholar
  25. 25.
    Cheng YC, Lin H, Huang MJ, Chow JM, Lin S, Liu HE (2007) Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res 31:1403–1411PubMedCrossRefGoogle Scholar
  26. 26.
    Ulasov IV, Nandi S, Dey M, Sonabend AM, Lesniak MS (2010) Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy. Mol Med 17:103–112PubMedGoogle Scholar
  27. 27.
    Metting Z, Rodiger LA, Stewart RE, Oudkerk M, De Keyser J, van der Naalt J (2009) Perfusion computed tomography in the acute phase of mild head injury: regional dysfunction and prognostic value. Ann Neurol 66:809–816PubMedCrossRefGoogle Scholar
  28. 28.
    Glover LE, Newton K, Krishnan G, Bronson R, Boyle A, Krivickas LS, Brown RH Jr (2010) Dysferlin overexpression in skeletal muscle produces a progressive myopathy. Ann Neurol 67:384–393PubMedGoogle Scholar
  29. 29.
    Perier C, Bove J, Dehay B, Jackson-Lewis V, Rabinovitch PS, Przedborski S, Vila M (2010) Apoptosis-inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins. Ann Neurol 68:184–192PubMedGoogle Scholar
  30. 30.
    Arbogast S, Beuvin M, Fraysse B, Zhou H, Muntoni F, Ferreiro A (2009) Oxidative stress in SEPN1-related myopathy: from pathophysiology to treatment. Ann Neurol 65:677–686PubMedCrossRefGoogle Scholar
  31. 31.
    Kazi AA, Lang CH (2010) PRAS40 regulates protein synthesis and cell cycle in C2C12 myoblasts. Mol Med 16:359–371PubMedCrossRefGoogle Scholar
  32. 32.
    Fan Y, Shen F, Frenzel T, Zhu W, Ye J, Liu J, Chen Y, Su H, Young WL, Yang GY (2010) Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol 67:488–497PubMedCrossRefGoogle Scholar
  33. 33.
    Fribley A, Zeng Q, Wang CY (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 24:9695–9704PubMedCrossRefGoogle Scholar
  34. 34.
    Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G (2001) The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 276:31674–31683PubMedCrossRefGoogle Scholar
  35. 35.
    Kaiser M, Zavrski I, Sterz J, Jakob C, Fleissner C, Kloetzel PM, Sezer O, Heider U (2006) The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. Haematologica 91:248–251PubMedGoogle Scholar
  36. 36.
    Kuendgen A, Gattermann N (2007) Valproic acid for the treatment of myeloid malignancies. Cancer 110:943–954PubMedCrossRefGoogle Scholar
  37. 37.
    Jabs T (1999) Reactive oxygen intermediates as mediators of programmed cell death in plants and animals. Biochem Pharmacol 57:231–245PubMedCrossRefGoogle Scholar
  38. 38.
    Nishioka C, Ikezoe T, Yang J, Koeffler HP, Yokoyama A (2008) Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell. Leukemia 22:1449–1452PubMedCrossRefGoogle Scholar
  39. 39.
    Yu C, Dasmahapatra G, Dent P, Grant S (2005) Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. Leukemia 19:1579–1589PubMedCrossRefGoogle Scholar
  40. 40.
    Braun T, Carvalho G, Coquelle A, Vozenin MC, Lepelley P, Hirsch F, Kiladjian JJ, Ribrag V, Fenaux P, Kroemer G (2006) NF-kappaB constitutes a potential therapeutic target in high-risk myelodysplastic syndrome. Blood 107:1156–1165PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ai-Hua Wang
    • 1
  • Lin Wei
    • 1
  • Li Chen
    • 1
  • Shu-Qing Zhao
    • 1
  • Wei-Li Wu
    • 1
  • Zhi-Xiang Shen
    • 1
  • Jun-Min Li
    • 1
  1. 1.Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of MedicineShanghaiChina

Personalised recommendations