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Immunosuppressors and reversion of multidrug-resistance

Nassera Aouali1, Lahcen Eddabra, Jérôme Macadré

  • 1Roswell Park Cancer Institute, Department of Cancer Genetique, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Critical Reviews in Oncology/Hematology
|June 28, 2005
PubMed

Insights

Multidrug resistance (MDR) in cancer therapy can be reversed by agents like cyclosporin A (CSA) and PSC833. These compounds modulate ATP-binding cassette transporters and impact ceramide metabolism, enhancing cancer cell death.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Drug resistance, particularly multidrug resistance (MDR), is a primary cause of cancer therapy failure.
  • ATP-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp), mediate MDR by actively effluxing anticancer drugs.
  • Modulating Pgp and ABC transporters to overcome MDR is a significant therapeutic challenge.

Purpose of the Study:

  • To investigate the efficacy of MDR modulators, including cyclosporin A (CSA) and its derivative PSC833, in reversing Pgp-mediated drug resistance.
  • To explore the mechanisms by which CSA and PSC833 affect cancer cell apoptosis, focusing on ceramide metabolism.
  • To assess the clinical relevance of MDR modulators targeting ABC transporters.

Main Methods:

  • Review of laboratory models and clinical trial data for CSA and PSC833 in reversing MDR.
  • Analysis of the impact of CSA and PSC833 on ceramide synthesis, glycosylation, and storage.
  • Evaluation of emerging MDR modulators like VX710 for broad ABC transporter targeting.

Main Results:

  • CSA demonstrated proof-of-concept for MDR reversal in early clinical trials (myeloma, leukemia) but showed less convincing outcomes in later phases.
  • PSC833, a more potent non-immunosuppressive derivative, showed promise but required dose reduction of co-administered anticancer agents.
  • Both CSA and PSC833 influence ceramide metabolism; PSC833 stimulates ceramide synthesis enhancing apoptosis, while CSA inhibits ceramide glucosylation, modulating MDR phenotype.

Conclusions:

  • MDR modulators like CSA and PSC833 offer potential strategies to overcome drug resistance in cancer.
  • Understanding the interplay between ABC transporters and ceramide metabolism is crucial for developing effective MDR reversal agents.
  • New modulators targeting multiple ABC transporters, such as VX710, hold promise for treating malignancies with complex efflux pump expression.

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