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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3584-3593.
Prepublished online as a Blood First Edition Paper on July 28, 2005; DOI 10.1182/blood-2005-02-0711.
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Submitted February 22, 2005
Accepted July 15, 2005
PK11195, a peripheral benzodiazepine receptor (PBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a PBR-independent, direct transporter-modulating mechanism
Roland B Walter, Jason L Pirga, Michelle R Cronk, Sasha Mayer, Frederick R Appelbaum, and Deborah E Banker*
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* Corresponding author; email: rwalter{at}fhcrc.org.
The peripheral benzodiazepine receptor (pBR) ligand, PK11195, promotes mitochondrial apoptosis and blocks P-glycoprotein (Pgp)-mediated drug efflux to chemosensitize cancer cells at least as well or better than the Pgp modulator, cyclosporine A (CSA). We now show that PK11195 broadly inhibits ATP-binding cassette (ABC) transporters in hematologic cancer cell lines and primary leukemia cell samples, including multi-drug resistance protein (MRP), breast cancer resistance protein (BCRP), and/or Pgp. Ectopic expression models confirmed that pBR can directly mediate chemosensitizing by PK11195, presumably via mitochondrial activities, but showed that pBR expression is unnecessary to PK11195-mediated efflux inhibition. PK11195 binds plasma membrane sites in Pgp-expressing cells, stimulates Pgp-associated ATPase activity, and causes conformational changes in Pgp, suggesting that PK11195 modulates Pgp-mediated efflux by direct transporter interaction(s). PK11195 and CSA bind non-competitively in Pgp-expressing cells, indicating that PK11195 interacts with Pgp at sites that are distinct from CSA-binding sites. Importantly, PK11195 concentrations that were effective in these in vitro assays can be safely achieved in patients. Since PK11195 promotes chemotherapy-induced apoptosis by a pBR-dependent mitochondrial mechanism, and broadly blocks drug efflux by an apparently pBR-independent, ABC transporter-dependent mechanism, PK11195 may be a useful clinical chemosensitizer in cancer patients.
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