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:

The role of P-glycoporotein in imatinib resistance

Leukemia volume 20, page 144 (2006)Cite this article

We read with great interest the report of Zong et al.1 in a recent issue of Leukemia dealing with the role of P-glycoprotein in imatinib resistance in vitro and in vivo. Using a transposon-based vector system we previously provided clear evidence that the specific knockdown of PgP using small interfering RNA (siRNA) resensitized imatinib-resitant cell lines to the growth inhibitory and cytotoxic effects of imatinib.2 Other groups underlined the importance of PgP for imatinib transport by showing that it eliminates imatinib from the intracellular space at concentrations ranging from 0.5 to 3 μg/ml.3 Although recognizing their impressive in vivo data, the animal model does not reflect the situation in malignant diseases, as under the latter condition the cancerous cells in general acquired resistance under chemotherapy and therefore express very high levels pf PgP. In contrast, the authors used stem cells of wild-type animals expressing ‘physiologic’ levels of Mdr1a/Mdr1b and compared these cells with cells from knockout mice (Mdr1a/Mdr1b-null). Moreover, the controversial in vitro data might also reflect different experimental approaches, as an isolated overexpression as carried out by Ferrao et al4 or by Zong et al.1 might be far more artificial when compared to the use of cells which upregulated PgP due to long-term culture in the presence of low-dose doxorubicin (which in our opinion more closely reflects the in vivo situation of acquiered drug resistance). We would even argue that the genetic modification using retroviral vectors might substantionally modify genetic programs by insertional mutagenesis. Finally, it is in our opinion critical that the authors used a model employing the mouse homologue of the human MDR1 gene. Thus, the same sensitivity to Glivec might also be due to a different substrate affinity to the mouse homologue.

Considering these points we feel that our data using the specificity of an siRNA approach strongly argue for the participation of PgP in chemoresistance to the cytotoxic effects of imatinib.

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

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

References

  1. Zong Y, Zhou S, Sorrentino BP . Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 2005; 19: 1590–1596.

    Article  CAS  Google Scholar 

  2. Rumpold H, Wolf AM, Gruenewald K, Gastl G, Gunsilius E, Wolf D . RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines. Exp Hematol 2005; 33: 767–775.

    Article  CAS  Google Scholar 

  3. Widmer N, Colombo S, Buclin T, Decosterd LA . Functional consequence of MDR1 expression on imatinib intracellular concentrations. Blood 2003; 102: 1142.

    Article  CAS  Google Scholar 

  4. Ferrao PT, Frost MJ, Siah SP, Ashman LK . Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood 2003; 102: 4499–4503.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Laboratory of Molecular Biology, Medical University Innsbruck, Austria

    H Rumpold

  2. Department of Hematology and Oncology, Laboratory of Tumorimmunology, Medical University Innsbruck, Austria

    A-M Wolf & D Wolf

Authors
  1. H Rumpold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A-M Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Rumpold.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rumpold, H., Wolf, AM. & Wolf, D. The role of P-glycoporotein in imatinib resistance. Leukemia 20, 144 (2006). https://doi.org/10.1038/sj.leu.2404001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404001

This article is cited by

Search

Advanced search

Quick links