%0 Journal Article
%T Anthracyclines, proteasome activity and multi-drug-resistance
%A Mirela R Fekete
%A William H McBride
%A Frank Pajonk
%J BMC Cancer
%D 2005
%I BioMed Central
%R 10.1186/1471-2407-5-114
%X Proteasome function was measured in cell lysates from ECV304 cells incubated with different doses of verapamil, doxorubicin, daunorubicin, idarubicin, epirubicin, topotecan, mitomycin C, and gemcitabine using a fluorogenic peptide assay. Proteasome function in living cells was monitored using ECV304 cells stably transfected with the gene for an ubiquitin/green fluorescent protein fusion protein. The ability of the proteasome inhibitor MG-132 to affect P-glycoprotein function was monitored by fluorescence due to accumulation of daunorubicin in P-glycoprotein overexpressing KB 8-5 cells.Verapamil, daunorubicin, doxorubicin, idarubicin, and epirubicin inhibited 26S chymotrypsin-like function in ECV304 extracts in a dose-dependent fashion. With the exception of daunorubicin, 20S proteasome function was also suppressed. The proteasome inhibitor MG-132 caused a dose-dependent accumulation of daunorubicin in KB 8-5 cells that overexpress P-glycoprotein, suggesting that it blocked P-glycoprotein function.Our data indicate that anthracyclines inhibit the 26S proteasome as well as P-glycoprotein. Use of inhibitors of either pathway in cancer therapy should take this into consideration and perhaps use it to advantage, for example during chemosensitization by proteasome inhibitors.Multi-drug-resistance (MDR) is a common reason for chemotherapy treatment failure in breast cancer, leukemia, and non-Hodgkin lymphoma patients. MDR can often be attributed to over-expression of the mdr1 gene that codes for an ATP-dependent, transmembrane P-glycoprotein (P-gp) efflux pump pathway, which rapidly exports man structurally un-related drugs from the cell, including anthracyclines [1,2].Numerous pre-clinical and clinical studies using P-gp modulating compounds like verapamil, cyclosporin A, reserpine, staurosporine, propafenone, phenoxazine, chloroquine, phenothiazine and their derivates have been undertaken to overcome MDR and several substances have been identified that are effective in v
%U http://www.biomedcentral.com/1471-2407/5/114