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Biochem Biophys Res Commun. 2007 Sep 21;361(2):549-54. Epub 2007 Jul 23.

Knockdown of PgP resensitizes leukemic cells to proteasome inhibitors.

Author information

1
Laboratory of Molecular Genetics, Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.

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 (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.

PMID:
17662692
DOI:
10.1016/j.bbrc.2007.07.049
[Indexed for MEDLINE]

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