期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 361, 期 2, 页码 549-554出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2007.07.049
关键词
cancer; drug resistance; proteasome inhibitors; drug transporter; PgP; MDR-1
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 253 ng/ml in MDR-1(+) to 9.7 ng/ml in MDR-1(-)cells) was much more dependent on MDR-1expression than Bortezomib (EC50 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. (c) 2007 Elsevier Inc. All rights reserved.
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