Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Nilotinib shows prolonged intracellular accumulation upon pulse-exposure: a novel mechanism for induction of apoptosis in CML cells

Leukemia volume 27, pages 1567–1570 (2013)Cite this article

Subjects

During the last decade, tyrosine kinase inhibitors (TKI) have fundamentally changed the landscape of cancer treatment.1, 2, 3, 4, 5, 6 Based upon preclinical data, it was believed that continuous kinase inhibition is a prerequisite for successful TKI treatment: It has been shown in a chronic myeloid leukemia (CML) mouse model that prolonged inhibition of BCR-ABL is necessary to eradicate the disease.7 In line with this, clinical trials identified a close relationship between imatinib serum trough-levels and clinical effectiveness.8, 9

In 2008, Shah et al.10 introduced the concept that transient potent BCR-ABL inhibition irreversibly commits CML cells to apoptosis. Consecutively, other groups published similar data on dasatinib and nilotinib.11, 12 Very recently, we have performed a comprehensive investigation on the molecular mechanisms involved in apoptosis induced upon transient kinase inhibition.13 Interestingly, cellular TKI accumulation and retention was identified as the underlying molecular mechanism of induction of apoptosis upon high-dose TKI (HD-TKI) pulse-exposure using either imatinib or dasatinib.13

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    Article  CAS  PubMed  Google Scholar 

  2. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res 2005; 11: 6414–6421.

    Article  CAS  PubMed  Google Scholar 

  3. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV . Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007; 13: 1367–1373.

    Article  CAS  PubMed  Google Scholar 

  4. Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542–2551.

    Article  PubMed  Google Scholar 

  5. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354: 2531–2541.

    Article  CAS  PubMed  Google Scholar 

  6. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E, Giardini R et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999; 91: 163–168.

    Article  CAS  PubMed  Google Scholar 

  8. Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008; 111: 4022–4028.

    Article  CAS  PubMed  Google Scholar 

  9. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496–3499.

    Article  CAS  PubMed  Google Scholar 

  10. Shah NP, Kasap C, Weier C, Balbas M, Nicoll JM, Bleickardt E et al. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell 2008; 14: 485–493.

    Article  CAS  PubMed  Google Scholar 

  11. Snead JL, O'Hare T, Adrian LT, Eide CA, Lange T, Druker BJ et al. Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis. Blood 2009; 114: 3459–3463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hiwase DK, White DL, Saunders VA, Kumar S, Melo JV, Hughes TP . Short-term intense Bcr-Abl kinase inhibition with nilotinib is adequate to trigger cell death in BCR-ABL(+) cells. Leukemia 2009; 23: 1205–1206.

    Article  CAS  PubMed  Google Scholar 

  13. Lipka DB, Wagner M-C, Dziadosz M, Schnöder T, Heidel F, Schemionek M et al. Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. PLoS One 2012; 7: e40853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hegedűs C, Özvegy-Laczka C, Apáti Á, Magócsi M, Német K, Őrfi L et al. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 2009; 158: 1153–1164.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dohse M, Scharenberg C, Shukla S, Robey RW, Volkmann T, Deeken JF et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Disposition 2010; 38: 1371–1380.

    Article  CAS  Google Scholar 

  16. Dziadosz M, Wagner M-C, Lipka DB, Fischer T, Bartels H . High-performance liquid chromatography with ultraviolet detection and protein precipitation as a way of quantitative determination of nilotinib with and without internal standard. J Liq Chromatogr Relat Techno 2012.

  17. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129–141.

    Article  CAS  PubMed  Google Scholar 

  18. Manley PW, Cowan-Jacob S, Fendrich G, Liebetanz J, Mestan J, Martin N, Fabbro D . 100th Annual Meeting of the American Association for Cancer Research; 18–22 April, 2009; Abstract no. 3715.

  19. Manley PW, Cowan-Jacob SW, Fendrich G, Jahnke W, Fabbro D . Nilotinib, in comparison to both dasatinib and imatinib, possesses a greatly prolonged residence time when bound to the BCR-ABL kinase SH1 domain. Blood (ASH Annu Meet Abstr) 2011; 118: 1674.

    Google Scholar 

Download references

Acknowledgements

This work was supported by research funds granted by Novartis Pharma GmbH (to DBL), by the ‘Wilhelm-Sander-Stiftung’ (No 2011.079.1 to FH, DBL, and TF) and by the ‘Deutsche Forschungsgemeinschaft’ (GRK-1167, P17-2 to TF and SFB-854/1, TP20 to TF).

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, University Medical Center, Otto-von-Guericke-University, Magdeburg, Germany

    M-C Wagner, F Heidel, T Fischer & D B Lipka

  2. Institute of Forensic Medicine, University Medical Center, Otto-von-Guericke-University, Magdeburg, Germany

    M Dziadosz

  3. Department of Haematology, Centre of Cancer Biology–IMVS, Adelaide, South Australia, Australia

    J V Melo

Authors
  1. M-C Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Dziadosz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J V Melo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Heidel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D B Lipka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D B Lipka.

Ethics declarations

Competing interests

DBL received research funding from Novartis and honoraria from Novartis and BMS; FH and TF received honoraria from Novartis. All other authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wagner, MC., Dziadosz, M., Melo, J. et al. Nilotinib shows prolonged intracellular accumulation upon pulse-exposure: a novel mechanism for induction of apoptosis in CML cells. Leukemia 27, 1567–1570 (2013). https://doi.org/10.1038/leu.2012.364

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.364

This article is cited by

Search

Advanced search

Quick links