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.

  • Correspondence
  • Published:

P-glycoprotein as a therapeutic target: good news

Leukemia volume 16, pages 2169–2170 (2002)Cite this article

An Erratum to this article was published on 28 October 2002

Multidrug resistance (MDR) remains a critical reason for therapeutic failures in patients with various types of cancer including haematological malignancies. P-glycoprotein (Pgp), a transmembrane transporter capable of effluxing many xenobiotics out of the cell, is widely considered a major mechanism of MDR. Moreover, evidence is growing that emphasizes the role for Pgp as a general anti-apoptotic factor. On the other hand, multiplicity of determinants of drug resistance and little convincing data on the efficacy of Pgp modulators in clinical trials preclude oversimplification of the issue. The problem still remains to be solved whether inhibition of Pgp function is important not only for circumvention of MDR (ie sensitization of tumour cells to Pgp-transported chemotherapeutic drugs) but also for direct elimination of pleiotropically resistant cells.

In this issue of the journal, Lehne et al1 provide significant support for this concept. The authors demonstrate that the non-immunosuppressive cyclosporin PSC 833, the drug currently in clinical trials as a candidate MDR-reversing agent/Pgp blocker, increased the survival of mice by delaying the engraftment of MDR human leukaemia KG1a/200 cells. These cells expressed Pgp-mediated MDR as a result of prolonged selection for insensitivity to adriamycin and vincristine. Importantly, the antitumour effect was observed with clinically achievable blood concentrations of PSC 833, and no signs of systemic toxicity were found in animals. The doses of PSC 833 administered in vivo matched those that caused sub-maximal toxicity for cultured KG1a/200 cells. This study clearly shows that inhibition of Pgp with a single drug can cause marked antitumour effect.

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. Lehne G, Sørensen DR, Tjønnfjord GE, Beiske C, Hagve T-A, Rugstad HE, Clausen OPE . The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug resistant leukemia cells in xenotransplanted NOD-SCID mice Leukemia 2002 16: (in press)

  2. van Helvoort A, Smith AJ, Sprong H, Fritzsche I, Schinkel A, Borst P, van Meer G . MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine Cell 1996 87: 507–517

    Article  CAS  PubMed  Google Scholar 

  3. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM . Biochemical, cellular and pharmacological aspects of the multidrug transporter Annu Rev Pharmacol Toxicol 1999 39: 361–398

    Article  CAS  PubMed  Google Scholar 

  4. Laurent G, Jaffrézou J-P . Signaling pathways activated by daunorubicin Blood 2001 98: 913–924

    Article  CAS  PubMed  Google Scholar 

  5. Senchenkov A, Litvak DA, Cabot MC . Targeting ceramide metabolism – a strategy for overcoming drug resistance J Natl Cancer Inst 2001 93: 347–357

    Article  CAS  PubMed  Google Scholar 

  6. Nicholson KM, Quinn DM, Kellett GL, Warr JR . Preferential killing of multidrug-resistant KB cells by inhibitors of glucosylceramide synthase Br J Cancer 1999 81: 423–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shtil AA . Signal transduction pathways and transcriptional mechanisms as targets for prevention of emergence of multidrug resistance in human cancer cells Curr Drug Targets 2001 2: 57–77

    Article  CAS  PubMed  Google Scholar 

  8. Johnstone RW, Tainton KM, Ruefli AA, Froelich CJ, Cerruti L, Jane SM, Smyth MJ . P-glycoprotein does not protect cells against cytolysis induced by pore-forming proteins J Biol Chem 2001 276: 16667–16673

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Tumor Cell Genetics, N Blokhin Cancer Centre, Moscow, Russia

    AA Shtil

Authors
  1. AA Shtil
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shtil, A. P-glycoprotein as a therapeutic target: good news. Leukemia 16, 2169–2170 (2002). https://doi.org/10.1038/sj.leu.2402664

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402664

This article is cited by

Search

Advanced search

Quick links