Herbimycin A accelerates the induction of apoptosis following etoposide treatment or γ-irradiation of bcr/abl-positive leukaemia cells (original) (raw)

Oncogene volume 16, pages 1533–1542 (1998)Cite this article

Abstract

Philadelphia chromosome (Ph)-positive leukaemia cells express the chimeric bcr/abl oncoprotein, whose deregulated protein tyrosine kinase (PTK) activity antagonizes the induction of apoptosis by DNA damaging agents. Treatment of Ph-positive K562, TOM 1 and KCL-22 cells with etoposide for 2d induced cytosolic vacuolation, but not nuclear condensation or DNA fragmentation. The bcr/abl kinase-selective inhibitor herbimycin A increased the induction of nuclear apoptosis by etoposide or γ-radiation. The concentration of herbimycin required to synergize with etoposide was similar to that required to decrease the level of tyrosine phosphorylated proteins or of the protein tyrosine kinase activity of anti-abl immune complexes in K562 cells. The ability of herbimycin A to sensitize K562, TOM 1 or KCL-22 cells to apoptosis induction correlated with its ability to decrease the cellular content of phosphotyrosyl proteins in these Philadelphia-positive lines. Enhancement of nuclear apoptosis by herbimycin was not attributable to downregulation of the bcl-2 or bcl-XL anti-apoptotic proteins. In contrast, herbimycin protected Philadelphia-negative HL60 cells from apoptosis induction by etoposide and did not affect killing of NC37 and CEM cells. The data suggest that the induction of apoptosis is blocked in cells expressing the bcr/abl oncoprotein and that herbimycin A increases induction of programmed cell death following DNA damage. Selective PTK inhibitors may therefore be of value in securing the genetic death of Ph-positive leukaemia cells.

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

Access options

Subscribe to this journal

Receive 50 print issues and online access

$259.00 per year

only $5.18 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

Author information

Author notes

  1. Fiona A Riordan and Christopher A Bravery: FA Riordan and CA Bravery contributed equally to this work and are therefore joint first authors

Authors and Affiliations

  1. Department of Hematology, Royal Free Hospital School of Medicine, Pond Street, London, NW3 2QG, UK
    Fiona A Riordan, Christopher A Bravery, Kamuran Mengubas, Nandita Ray, Steven M Hart, A Victor Hoffbrand, Atul B Mehta & R Gitendra Wickremasinghe
  2. Department of Clinical Immunology, Royal Free Hospital School of Medicine, Pond Street, London, NW3 2QG, UK
    Nicola J Borthwick & Arne N Akbar

Authors

  1. Fiona A Riordan
    You can also search for this author inPubMed Google Scholar
  2. Christopher A Bravery
    You can also search for this author inPubMed Google Scholar
  3. Kamuran Mengubas
    You can also search for this author inPubMed Google Scholar
  4. Nandita Ray
    You can also search for this author inPubMed Google Scholar
  5. Nicola J Borthwick
    You can also search for this author inPubMed Google Scholar
  6. Arne N Akbar
    You can also search for this author inPubMed Google Scholar
  7. Steven M Hart
    You can also search for this author inPubMed Google Scholar
  8. A Victor Hoffbrand
    You can also search for this author inPubMed Google Scholar
  9. Atul B Mehta
    You can also search for this author inPubMed Google Scholar
  10. R Gitendra Wickremasinghe
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Riordan, F., Bravery, C., Mengubas, K. et al. Herbimycin A accelerates the induction of apoptosis following etoposide treatment or γ-irradiation of bcr/abl-positive leukaemia cells.Oncogene 16, 1533–1542 (1998). https://doi.org/10.1038/sj.onc.1201680

Download citation

Keywords