title: PK11195, a peripheral benzodiazepine receptor ligand, chemosensitizes acute myeloid leukemia cells to relevant therapeutic agents by more than one mechanism.
abstract: Like Bcl-2, peripheral benzodiazepine receptors (pBzRs) reside in mitochondrial pores, are frequently over-expressed in tumor cells, and can protect cells from apoptotic cell death. We now show that the high-affinity, pBzR-specific ligand, PK11195, chemosensitizes AML cells to relevant chemotherapeutics, but is relatively non-toxic as a single agent, and does not chemosensitize normal myeloid cells. PK11195 can block p-glycoprotein efflux in AMLs, contributing to increased daunomycin toxicity in efflux-competent AMLs, but can also sensitize AMLs to cytarabine and DNR-sensitize efflux-incompetent AMLs, presumably via mitochondrial pore effects documented in other models. Therefore, PK11195 might contribute to improved clinical outcomes in AML.
authors.affiliation: Clinical Research Division, FHCRC, D1-100, 1124 Columbia Street, Seattle, WA 98104, USA. dbanker@fhcrc.org
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Banker
authors.forename: John J
authors.initials: JJ
authors.lastname: Cooper
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: Finbarr E
authors.initials: FE
authors.lastname: Cotter
mesh_terms: D000208:Acute Disease; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008024:Ligands; D011963:Receptors, GABA-A / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; D003561:Cytarabine; C037850:PK 11195; D003630:Daunorubicin