title: 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.
abstract: 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 adenosine triphosphate (ATP)-binding cassette (ABC) transporters in hematologic cancer cell lines and primary leukemia-cell samples, including multidrug 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 adenosine triphosphatase (ATPase) activity, and causes conformational changes in Pgp, suggesting that PK11195 modulates Pgp-mediated efflux by direct transporter interaction(s). PK11195 and CSA bind noncompetitively 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. Because 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. rwalter@fhcrc.org
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: Jason L
authors.initials: JL
authors.lastname: Pirga
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Cronk
authors.forename: Sasha
authors.initials: S
authors.lastname: Mayer
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Banker
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D001693:Biological Transport, Active / Q000187:drug effects; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D058785:GABA-A Receptor Agonists; D018922:HL-60 Cells; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D058785:GABA-A Receptor Agonists; D007546:Isoquinolines; D008024:Ligands; D009363:Neoplasm Proteins; D011963:Receptors, GABA-A; D016572:Cyclosporine; C037850:PK 11195