Synergistic growth inhibitory effects of interferon-α and lovastatin on bcr-abl positive leukemic cells

  • Authors:
    • Carsten Müller-Tidow
    • Michael Kiehl
    • Jürgen R. Sindermann
    • Michael Probst
    • Nicola Banger
    • Michael Zühlsdorf
    • Ting-Chao Chou
    • Wolfgang E. Berdel
    • Hubert Serve
    • Olaf M. Koch
  • View Affiliations

  • Published online on: July 1, 2003     https://doi.org/10.3892/ijo.23.1.151
  • Pages: 151-158
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Abstract

The chimeric bcr-abl tyrosine kinase is of crucial pathogenic importance in chronic myeloid leukemia (CML). As shown, bcr-abl activates the ras pathway by phosphorylation of adapter proteins such as Grb-2 and Crkl. Functional inhibition of p21ras might partially inhibit the mitogenic signaling by bcr-abl. By depletion of cellular mevalonate pools, p21ras proteins can be rendered non-functional as a result of deficient post-translational protein farnesylation. We investigated the pharmacologic effect of mevalonate depletion by lovastatin in conjunction with interferon-α 2b (INF-α 2b) in bcr-abl positive K562 cells. At various concentrations, both drugs synergistically reduced cell proliferation of CML line K562 in a liquid culture system as well as clonal growth of colony forming units in a patient with newly diagnosed CML. Lovastatin and IFN-α 2b in combination led to cell cycle arrest and resulted in significant reduction of phosphorylation on tyrosine, serine, and threonine protein residues. IFN-α 2b alone showed little effect on protein phosphorylation but strongly enhanced lovastatin driven loss of phosphorylation. Subsequently, DNA fragmentation occurred in 50% of cells. In conclusion, exposure to IFN-α 2b and lovastatin synergistically inhibited proliferation of bcr-abl positive cells and resulted in loss of protein phosphorylation and subsequent apoptosis in K562 cells. Our in vitro model suggests further investigations are required of the potential value of HMG-CoA reductase inhibitors as adjunct to therapy of CML with interferon.

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July 2003
Volume 23 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Müller-Tidow, C., Kiehl, M., Sindermann, J.R., Probst, M., Banger, N., Zühlsdorf, M. ... Koch, O.M. (2003). Synergistic growth inhibitory effects of interferon-α and lovastatin on bcr-abl positive leukemic cells. International Journal of Oncology, 23, 151-158. https://doi.org/10.3892/ijo.23.1.151
MLA
Müller-Tidow, C., Kiehl, M., Sindermann, J. R., Probst, M., Banger, N., Zühlsdorf, M., Chou, T., Berdel, W. E., Serve, H., Koch, O. M."Synergistic growth inhibitory effects of interferon-α and lovastatin on bcr-abl positive leukemic cells". International Journal of Oncology 23.1 (2003): 151-158.
Chicago
Müller-Tidow, C., Kiehl, M., Sindermann, J. R., Probst, M., Banger, N., Zühlsdorf, M., Chou, T., Berdel, W. E., Serve, H., Koch, O. M."Synergistic growth inhibitory effects of interferon-α and lovastatin on bcr-abl positive leukemic cells". International Journal of Oncology 23, no. 1 (2003): 151-158. https://doi.org/10.3892/ijo.23.1.151