Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10767105 | Biochemical and Biophysical Research Communications | 2007 | 6 Pages |
Abstract
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 (EC50 from 253Â ng/ml in MDR-1+ to 9.7Â ng/ml in MDR-1â cells) was much more dependent on MDR-1 expression than Bortezomib (EC50 from 24.9Â ng/ml in MDR-1+ to 4.5Â ng/ml in MDR-1â 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.
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Authors
Holger Rumpold, Christina Salvador, Anna Maria Wolf, Herbert Tilg, Guenther Gastl, Dominik Wolf,