Annals of Hematology

, Volume 89, Issue 11, pp 1081–1087 | Cite as

Efficacy of MK-0457 and in combination with vorinostat against Philadelphia chromosome positive acute lymphoblastic leukemia cells

Original Article
First Online:
Received:
Accepted:

Abstract

Aurora kinases play a pivotal role in the regulator of mitotic processes during cell division and Aurora kinases are overexpressed in a number of human cancers. In this study, we examined the intracellular signaling of Aurora kinases inhibitor, MK-0457 (VX-680), in BCR-ABL positive cell lines and in primary samples. MK-0457 induced apoptosis. Caspase 3 and poly (ADP-ribose) polymerase (PARP) were activated and heat shock proteins were reduced. A combination of MK-0457 and histone deacetylase inhibitor, vorinostat, increased apoptosis. Caspase 3 and PARP were activated and phosphorylation of BCR-ABL, Lyn, and Crk-L were reduced. BCR-ABL and Aurora A and B were reduced after vorinostat treatment. Moreover, combination of vorinostat and MK-0457 synergistically increased the extent of apoptosis in primary acute lymphoblastic leukemia cells with T315I mutation. Our study increases insight into how MK-0457 may mediate its effects on BCR-ABL positive leukemia cells with T315I mutation, and information of potential therapeutic relevance.

Keywords

Acute lymphoblastic leukemia HDAC inhibitor Aurora kinase inhibitor T315I mutation 
This is a preview of subscription content, log in to check access.

Notes

Conflict of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Pui CH, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 345:166–178CrossRefGoogle Scholar
  2. 2.
    Jeha S (2009) New therapeutic strategies in acute lymphoblastic leukemia. Semin Hematol 46:76–88CrossRefPubMedGoogle Scholar
  3. 3.
    Pui CH, Robison LL, Look AT (2008) Acute lymphoblastic leukaemia. Lancet 371:1030–1043CrossRefPubMedGoogle Scholar
  4. 4.
    Pui CH, Jeha S (2007) New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 6:149–165CrossRefPubMedGoogle Scholar
  5. 5.
    Quintás-Cardama A, Kantarjian H, Cortes J (2007) Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov 6:834–848CrossRefPubMedGoogle Scholar
  6. 6.
    Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, Lange T, Hochhaus A, Wystub S, Brück P, Hoelzer D, Ottmann OG (2007) Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 110:727–734CrossRefPubMedGoogle Scholar
  7. 7.
    Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN Jr, Gandara DR (2008) Aurora kinases as anticancer drug targets. Clin Cancer Res 14:1639–1648CrossRefPubMedGoogle Scholar
  8. 8.
    Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ (2007) MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109:500–502CrossRefPubMedGoogle Scholar
  9. 9.
    Ohyashiki K, Miyauchi J, Ohyashiki JH, Saito M, Yaguchi M, Inatomi Y, Nakazawa S, Waca H, Mizutani S, Matsuo Y et al (1993) Interleukin-7 enhances colony growth and induces CD20 antigen of a Ph+ acute lymphoblastic leukemia cell line, OM9;22. Leukemia 7:1034–1040PubMedGoogle Scholar
  10. 10.
    Kimura S, Naito H, Segawa H, Kuroda J, Yuasa T, Sato K, Yokota A, Kamitsuji Y, Kawata E, Ashihara E, Nakaya Y, Naruoka H, Wakayama T, Nasu K, Asaki T, Niwa T, Hirabayashi K, Maekawa T (2005) NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood 106:3948–3954CrossRefPubMedGoogle Scholar
  11. 11.
    Okabe S, Tauchi T, Ohyashiki K (2008) Characteristics of dasatinib- and imatinib-resistant chronic myelogenous leukemia cells. Clin Cancer Res 14:6181–6186CrossRefPubMedGoogle Scholar
  12. 12.
    Okabe S, Tauchi T, Ohyashiki K, Broxmeyer HE (2006) Stromal-cell-derived factor-1/CXCL12-induced chemotaxis of a T cell line involves intracellular signaling through Cbl and Cbl-b and their regulation by Src kinases and CD45. Blood Cells Mol Dis 36:308–314CrossRefPubMedGoogle Scholar
  13. 13.
    Okabe S, Fukuda S, Kim YJ, Niki M, Pelus LM, Ohyashiki K, Pandolfi PP, Broxmeyer HE (2005) Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1. Blood 105:474–480CrossRefPubMedGoogle Scholar
  14. 14.
    Xu WS, Parmigiani RB, Marks PA PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26:5541–5552CrossRefPubMedGoogle Scholar
  15. 15.
    Banerji U (2009) Heat shock protein 90 as a drug target: some like it hot. Clin Cancer Res 15:9–14CrossRefPubMedGoogle Scholar
  16. 16.
    Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP (2002) High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 99:3472–3475CrossRefPubMedGoogle Scholar
  17. 17.
    Deininger M, Buchdunger E, Druker BJ (2005) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653CrossRefPubMedGoogle Scholar
  18. 18.
    Okabe S, Tauchi T, Nakajima A, Sashida G, Gotoh A, Broxmeyer HE, Ohyashiki JH, Ohyashiki K (2007) Depsipeptide (FK228) preferentially induces apoptosis in BCR/ABL-expressing cell lines and cells from patients with chronic myelogenous leukemia in blast crisis. Stem Cells Dev 16:503–514CrossRefPubMedGoogle Scholar
  19. 19.
    Okabe S, Tauchi T, Ohyashiki JH, Ohyashiki K (2009) Mechanism of MK-0457 efficacy against BCR-ABL positive leukemia cells. Biochem Biophys Res Commun 380:775–779CrossRefPubMedGoogle Scholar
  20. 20.
    Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ (2009) Targeting HSP90 for cancer therapy. Br J Cancer 100:1523–1529CrossRefPubMedGoogle Scholar
  21. 21.
    Fiskus W, Wang Y, Joshi R, Rao R, Yang Y, Chen J, Kolhe R, Balusu R, Eaton K, Lee P, Ustun C, Jillella A, Buser CA, Peiper S, Bhalla K (2008) Concomitant treatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells. Clin Cancer Res 14:6106–6115CrossRefPubMedGoogle Scholar
  22. 22.
    Dai Y, Chen S, Venditti CA, Pei XY, Nguyen TK, Dent P, Grant S (2008) Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate. Blood 112:793–804CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Seiichi Okabe
    • 1
  • Tetsuzo Tauchi
    • 1
  • Kazuma Ohyashiki
    • 1
  1. 1.First Department of Internal MedicineTokyo Medical UniversityTokyoJapan

Personalised recommendations