Skip to main content
SpringerLink
Log in

Bortezomib suppresses the growth of leukemia cells with Notch1 overexpression in vivo and in vitro

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Bortezomib has been widely used in the treatment of various cancers; however, its exact mechanisms of action are not fully understood, particularly in acute T lymphoblast leukemia (T-ALL). Here, we visualize the anti-leukemia effect of bortezomib in both human T-ALL cell line and animal models. In vitro study, a human T-ALL cell line bearing Notch1 mutations, MOLT-4, was treated with bortezomib. At clinically achievable concentrations, bortezomib inhibited cell growth by inducing G1 phase arrest and apoptosis with a dose-dependent manner. A murine tumor xenograft model was achieved by subcutaneous injection of MOLT-4 cells for in vivo study. Administration of bortezomib significantly reduced tumor mass volume when compared with controls. Of note, bortezomib inhibited growth of leukemia cells in a Notch1-induced murine T-ALL model, and the life span of leukemia-bearing mice was markedly increased. Further studies revealed that bortezomib led to inhibited expression of Notch1 target genes. Taken together, our results demonstrate that bortezomib shows significant anti-leukemia effect in T-ALL bearing Notch1 mutations in vitro and in vivo. The present study provides evidence that bortezomib might be a candidate therapeutic reagent in the treatment of T-ALL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Pui CH, Robison LL, Look AT (2008) Acute lymphoblastic leukaemia. Lancet 371:1030–1043

    Article  PubMed  CAS  Google Scholar 

  2. Bazarbachi A, Ghez D, Lepelletier Y, Nasr R, de The H, El-Sabban ME, Hermine O (2004) New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol 5:664–672

    Article  PubMed  CAS  Google Scholar 

  3. Liu H, Chi AW, Arnett KL, Chiang MY, Xu L, Shestova O, Wang H, Li YM, Bhandoola A, Aster JC, Blacklow SC, Pear WS (2010) Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 24:2395–2407

    Article  PubMed  CAS  Google Scholar 

  4. Mansur MB, Hassan R, Barbosa TC, Splendore A, Jotta PY, Yunes JA, Wiemels JL, Pombo-de-Oliveira MS (2012) Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia. BMC Cancer 12:9

    Article  PubMed  CAS  Google Scholar 

  5. Espinosa L, Cathelin S, D’Altri T, Trimarchi T, Statnikov A, Guiu J, Rodilla V, Ingles-Esteve J, Nomdedeu J, Bellosillo B, Besses C, Abdel-Wahab O, Kucine N, Sun SC, Song G, Mullighan CC, Levine RL, Rajewsky K, Aifantis I, Bigas A (2010) The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell 18:268–281

    Article  PubMed  CAS  Google Scholar 

  6. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML, Kee BL, Ferrando A, Miele L, Aifantis I (2007) Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13:70–77

    Article  PubMed  CAS  Google Scholar 

  7. Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M, Fettucciari K, Bartoli A, Coaccioli S, Screpanti I, Marconi P (2009) Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 113:856–865

    Article  PubMed  CAS  Google Scholar 

  8. Song LL, Peng Y, Yun J, Rizzo P, Chaturvedi V, Weijzen S, Kast WM, Stone PJ, Santos L, Loredo A, Lendahl U, Sonenshein G, Osborne B, Qin JZ, Pannuti A, Nickoloff BJ, Miele L (2008) Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 27:5833–5844

    Article  PubMed  CAS  Google Scholar 

  9. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917

    Article  PubMed  CAS  Google Scholar 

  10. Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M (2007) Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood 109:2767–2772

    PubMed  CAS  Google Scholar 

  11. Ramalingam SS, Davies AM, Longmate J, Edelman MJ, Lara PN Jr, Vokes EE, Villalona-Calero M, Gitlitz B, Reckamp K, Salgia R, Wright JJ, Belani CP, Gandara DR (2011) Bortezomib for patients with advanced-stage bronchioloalveolar carcinoma: a California Cancer Consortium Phase II study (NCI 7003). J Thorac Oncol 6:1741–1745

    Article  PubMed  Google Scholar 

  12. Pitts TM, Morrow M, Kaufman SA, Tentler JJ, Eckhardt SG (2009) Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. Mol Cancer Ther 8:342–349

    Article  PubMed  CAS  Google Scholar 

  13. Schmid P, Kuhnhardt D, Kiewe P, Lehenbauer-Dehm S, Schippinger W, Greil R, Lange W, Preiss J, Niederle N, Brossart P, Freier W, Kummel S, Van de Velde H, Regierer A, Possinger K (2008) A phase I/II study of bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines. Ann Oncol 19:871–876

    Article  PubMed  CAS  Google Scholar 

  14. Dreicer R, Petrylak D, Agus D, Webb I, Roth B (2007) Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Clin Cancer Res 13:1208–1215

    Article  PubMed  CAS  Google Scholar 

  15. Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT (2002) Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99:2369–2378

    Article  PubMed  CAS  Google Scholar 

  16. Wang M, Chen Y, Zhang Y, Zhang L, Lu X, Chen Z (2011) Mannan-binding lectin directly interacts with Toll-like receptor 4 and suppresses lipopolysaccharide-induced inflammatory cytokine secretion from THP-1 cells. Cell Mol Immunol 8:265–275

    Article  PubMed  CAS  Google Scholar 

  17. Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, Krishnamoorthy V, Bhasin M, Capobianco AJ, Kelliher MA (2006) Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 26:8022–8031

    Article  PubMed  CAS  Google Scholar 

  18. Raina D, Pandey P, Ahmad R, Bharti A, Ren J, Kharbanda S, Weichselbaum R, Kufe D (2005) c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem 280:11147–11151

    Article  PubMed  CAS  Google Scholar 

  19. Hu X, Shen H, Tian C, Yu H, Zheng G, XuFeng R, Ju Z, Xu J, Wang J, Cheng T (2009) Kinetics of normal hematopoietic stem and progenitor cells in a Notch1-induced leukemia model. Blood 114:3783–3792

    Article  PubMed  CAS  Google Scholar 

  20. De Keersmaecker K, Lahortiga I, Mentens N, Folens C, Van Neste L, Bekaert S, Vandenberghe P, Odero MD, Marynen P, Cools J (2008) In vitro validation of gamma-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. Haematologica 93:533–542

    Article  PubMed  Google Scholar 

  21. Kindler T, Cornejo MG, Scholl C, Liu J, Leeman DS, Haydu JE, Frohling S, Lee BH, Gilliland DG (2008) K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. Blood 112:3373–3382

    Article  PubMed  CAS  Google Scholar 

  22. Samon JB, Castillo-Martin M, Hadler M, Ambesi-Impiobato A, Paietta E, Racevskis J, Wiernik PH, Rowe JM, Jakubczak J, Randolph S, Cordon-Cardo C, Ferrando AA (2012) Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol Cancer Ther 11:1565–1575

    Article  PubMed  CAS  Google Scholar 

  23. Saitoh Y, Yamamoto N, Dewan MZ, Sugimoto H, Martinez Bruyn VJ, Iwasaki Y, Matsubara K, Qi X, Saitoh T, Imoto I, Inazawa J, Utsunomiya A, Watanabe T, Masuda T, Yamaoka S (2008) Overexpressed NF-kappaB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells. Blood 111:5118–5129

    Article  PubMed  CAS  Google Scholar 

  24. Sanda T, Asamitsu K, Ogura H, Iida S, Utsunomiya A, Ueda R, Okamoto T (2006) Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. Leukemia 20:590–598

    Article  PubMed  CAS  Google Scholar 

  25. Aster JC (2005) Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities. Int J Hematol 82:295–301

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported by an NFSC grant (nos 30800488 and 30900644), Excellent young scholarship from Shanghai Health Bureau (XYQ 2011007), and Shanghai Science and Technology Committee (06411951). We appreciate the valuable comments from other members of our laboratories.

Author information

Authors and Affiliations

  1. Department of Hematology, Institute of Hematology, PLA, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Chongmei Huang, Xiaoxia Hu, Libing Wang, Shuqing Lü, Hui Cheng, Xianmin Song, Jianmin Wang & Jianmin Yang

Authors
  1. Chongmei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoxia Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Libing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuqing Lü
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xianmin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianmin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jianmin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianmin Yang.

Additional information

Chongmei Huang, Xiaoxia Hu and Libing Wang contributed equally to the article.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, C., Hu, X., Wang, L. et al. Bortezomib suppresses the growth of leukemia cells with Notch1 overexpression in vivo and in vitro. Cancer Chemother Pharmacol 70, 801–809 (2012). https://doi.org/10.1007/s00280-012-1953-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-1953-4

Keywords

Search

Navigation