Knockdown of PgP resensitizes leukemic cells to proteasome inhibitors.
Overexpression of MDR-1 represents a critical mechanism of drug resistance in cancer. Proteasome inhibitors recently entered the clinic for treatment of multiple myeloma. We provide evidence that the proteasome-inhibitors Bortezomib and MLN273 are both substrates of MDR-1 by using knockdown of MDR-1 via a transposon-based vector system stably expressing siRNA against MDR-1 in MDR-1-overexpressing K562/Dox cells. Notably, the efficacy of MLN273 (EC(50) from 253 ng/ml in MDR-1(+) to 9.7 ng/ml in MDR-1(-) cells) was much more dependent on MDR-1 expression than Bortezomib (EC(50) from 24.9 ng/ml in MDR-1(+) to 4.5 ng/ml in MDR-1(-) cells). Growth inhibition in MDR-1 negative cells was in part due to increased rate of apoptosis. The enhanced inhibitory effect on the proteasome by loss of MDR-1 was corroborated by a reduced proteasomal activity. Our report provides evidence that MLN273 and, to a lesser degree, Bortezomib are both MDR-1-substrates, which might be relevant for drug-resistance in cancer.
Rumpold
Holger
H
Laboratory of Molecular Genetics, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.
Salvador
Christina
C
Wolf
Anna Maria
AM
Tilg
Herbert
H
Gastl
Guenther
G
Wolf
Dominik
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D061988:Proteasome Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001897:Boronic Acids; D004151:Dipeptides; C509910:N-(4-morpholine)carbonyl-beta-(1-naphthyl)-alanyl-leucine boronic acid; D061988:Proteasome Inhibitors