RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines.
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.
Rumpold
Holger
H
Laboratory of Tumorbiology and Angiogenesis, Division of Hematology and Oncology, Medical University of Innsbruck, Austria.
Wolf
Anna M
AM
Gruenewald
Kurt
K
Gastl
Guenther
G
Gunsilius
Eberhard
E
Wolf
Dominik
D
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*
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