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Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Izabela Mynarczuk-Biay^1,4, Heike Roeckmann⁶, Ulrike Kuckelkorn¹, Boris Schmidt⁷, Sumaira Umbreen⁷, Jakub Gob⁵, Antje Ludwig², Christina Montag³, Lüder Wiebusch³, Christian Hagemeier³, Dirk Schadendorf⁶, Peter-M. Kloetzel¹ and Ulrike Seifert¹

¹ Institut fuer Biochemie Charité-Universitaetsmedizin Berlin; ² Medizinische Klinik und Poliklinik, Schwerpunkt Kardiologie, Angiologie, Pneumologie Charité-Universitaetsmedizin; ³ Abteilung fuer Paediatrie, Labor fuer Molekulare Biologie, Charité-Universitaetsmedizin, Berlin, Germany; ⁴ Department of Histology and Embryology, Centre for Biostructure Research, The Medical University of Warsaw; ⁵ Department of Immunology, Centre for Biostructure Research, The Medical University of Warsaw, Warsaw, Poland; ⁶ Klinische Kooperationseinheit fuer Dermatoonkologie, Abteilung fuer Dermatologie, Universitaetsklinikum Mannheim, Mannheim, Germany; and ⁷ Clemens-Schoepf-Institute fuer Organische Chemie und Biochemie TU Darmstadt, Darmstadt, Germany

Requests for reprints: Peter-M. Kloetzel, Institut fuer Biochemie, Charité-Universitaetsmedizin Berlin, Monbijoustr.2, 10117 Berlin, Germany. Phone: 49-30450528232; Fax: 49-30450528921; E-mail: p-m.kloetzel{at}charite.de.

Resistance of tumor cells to cisplatin is a common feature frequently encountered during chemotherapy against melanoma caused by various known and unknown mechanisms. To overcome drug resistance toward cisplatin, a targeted treatment using alternative agents, such as proteasome inhibitors, has been investigated. This combination could offer a new therapeutic approach. Here, we report the biological effects of proteasome inhibitors on the parental cisplatin-sensitive MeWo human melanoma cell line and its cisplatin-resistant MeWo_cis1 variant. Our experiments show that proteasome inhibitor treatment of both cell lines impairs cell viability at concentrations that are not toxic to primary human fibroblasts in vitro. However, compared with the parental MeWo cell line, significantly higher concentrations of proteasome inhibitor are required to reduce cell viability of MeWo_cis1 cells. Moreover, whereas proteasome activity was inhibited to the same extent in both cell lines, IB degradation and nuclear factor-B (NF-B) activation in MeWo_cis1 cells was proteasome inhibitor independent but essentially calpain inhibitor sensitive. In support, a calpain-specific inhibitor impaired NF-B activation in MeWo_cis1 cells. Here, we show that cisplatin resistance in MeWo_cis1 is accompanied by a change in the NF-B activation pathway in favor of calpain-mediated IB degradation. Furthermore, combined exposure to proteasome and calpain inhibitor resulted in additive effects and a strongly reduced cell viability of MeWo_cis1 cells. Thus, combined strategies targeting distinct proteolytic pathways may help to overcome mechanisms of drug resistance in tumor cells. (Cancer Res 2006; 66(15): 7598-605)

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