title: RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines.
abstract: OBJECTIVE
  Resistance to therapeutic drugs is a frequent phenomenon in hematologic malignancies, causing treatment failure in patients with leukemias and lymphomas. Overexpression of the multidrug-resistance gene (MDR-1) and its translational product P-glycoprotein (PgP) represents one mechanism of fatal drug resistance.
  
  
  METHODS
  We constructed a nonviral, transposon-based vector system for the stable knockdown of PgP in chronic myeloid leukemia cell lines resistant to imatinib and doxorubicin.
  
  
  RESULTS
  Using this strategy, PgP expression was completely knocked down 72 hours after vector inoculation and lasted for several months. Cellular efflux of the PgP substates rhodamine and doxorubicin was abolished. Vector-treated cells were resensitized to imatinib- and doxorubicin-induced cell death.
  
  
  CONCLUSIONS
  Using chronic myeloid leukemia as a model, we show that PgP-mediated resistance to imatinib and anthracyclines can be durably reversed by nonviral, transposon-based knockdown of PgP in malignant cells.
authors.affiliation: Laboratory of Tumorbiology and Angiogenesis, Division of Hematology and Oncology, Medical University of Innsbruck, Austria.
authors.forename: Holger
authors.initials: H
authors.lastname: Rumpold
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wolf
authors.forename: Kurt
authors.initials: K
authors.lastname: Gruenewald
authors.forename: Guenther
authors.initials: G
authors.lastname: Gastl
authors.forename: Eberhard
authors.initials: E
authors.lastname: Gunsilius
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D018943:Anthracyclines / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D001549:Benzamides; D045744:Cell Line, Tumor; D004251:DNA Transposable Elements; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010879:Piperazines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D034741:RNA, Small Interfering; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D000970:Antineoplastic Agents; D001549:Benzamides; D004251:DNA Transposable Elements; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000068877:Imatinib Mesylate