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Nuclear Factor-B Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

Departments of Pharmacology (S.B., C.A.R., M.G., B.S., H.K.K.) and Pediatric Oncology (J.S., J.F.B.), Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Institute of Pharmacy (C.A.R.), Ernst Moritz Arndt-University, Greifswald, Germany

Anthracyclines such as doxorubicin remain among the most effective agents for the treatment of solid tumors and hematological malignancies. To overcome dose-limiting side effects like cardiotoxicity, an intensive effort has been undertaken to develop promising doxorubicin prodrugs that are specifically activated at the tumor site. One approach is the application of peptide prodrugs of doxorubicin. The enzyme cathepsin B catalyzes the activation of these prodrugs, and hence, the regulation of cathepsin B by antitumor agents could influence the efficacy of peptide prodrugs using this protease. In the present investigation, the effects of doxorubicin on cathepsin B expression in the human cervix carcinoma cell line HeLa were examined. Exposure to doxorubicin induced a time- and dose-dependent up-regulation of cathepsin B expression on mRNA, protein, and activity levels. In the cathepsin B gene promoter region, a potential nuclear factor B (NF-B) binding site could be identified. Pretreatment of HeLa cells with specific NF-B inhibitors abrogated the induction of cathepsin B expression. Doxorubicin-induced degradation of the inhibitory protein IB could be prevented by pretreatment with a specific proteasome inhibitor, resulting in a significant reduction of the doxorubicin-induced cathepsin B expression. Finally, binding of NF-B subunits p50 and p65 to the NF-B binding site in the cathepsin B gene promoter region could be demonstrated by electrophoretic mobility shift assay. In summary, our data clearly indicate that doxorubicin induces cathepsin B expression and activity via NF-B. These findings contribute to a better understanding of tumor targeting with peptide prodrugs and help to define a possible mechanism of doxorubicin toxicity in tumor cells.

Address correspondence to: Dr. Heyo K. Kroemer, Institute of Pharmacology, University of Greifswald, Friedrich-Loeffler-Str. 23D, 17487 Greifswald, Germany. E-mail: kroemer{at}uni-greifswald.de

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