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Bicalutamide failure in prostate cancer treatment: involvement of Multi Drug Resistance proteins

Nicola Antonio Colabufo1, Vincenzo Pagliarulo, Francesco Berardi

  • 1Dipartimento Farmacochimico, Universita' degli Studi di Bari, via Orabona 4, 70125, Bari, Italy. colabufo@farmchim.uniba.it

European Journal of Pharmacology
|November 11, 2008
PubMed

Insights

Drug resistance in prostate cancer may involve ATP-binding cassette pumps. Inhibiting these pumps, like P-glycoprotein and BCRP, can restore bicalutamide

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Prolonged bicalutamide treatment for prostate cancer can lead to relapse with more aggressive disease.
  • Androgen receptor mutation is a known cause of bicalutamide failure.
  • An alternative mechanism involving ATP-binding cassette (ABC) pumps extruding bicalutamide was hypothesized.

Purpose of the Study:

  • To investigate the role of ABC pumps (P-glycoprotein, BCRP, MRP1) in bicalutamide resistance.
  • To evaluate the efficacy of an ABC pump inhibitor (MC18) in overcoming bicalutamide resistance.

Main Methods:

  • Utilized androgen-dependent (LnCap) and androgen-independent (PC-3) prostate cancer cell lines.
  • Assessed bicalutamide's antiproliferative effects with and without the ABC pump inhibitor MC18.
  • Employed stable transfected MDCK cells overexpressing individual ABC pumps to determine transporter contribution.

Main Results:

  • MC18 significantly ameliorated bicalutamide's antiproliferative effect in LnCap cells and restored it in PC-3 cells.
  • P-glycoprotein and BCRP were identified as key transporters involved in bicalutamide efflux.
  • MRP1 was found to be unable to bind or efflux bicalutamide.

Conclusions:

  • ABC pumps, particularly P-glycoprotein and BCRP, contribute to bicalutamide resistance in prostate cancer.
  • Inhibiting these efflux pumps represents a potential strategy to overcome treatment failure.
  • Further research into combination therapies involving bicalutamide and ABC pump inhibitors is warranted.

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