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

Abstract

<div>Abstract<p>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<sub>cis1</sub> 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 <i>in vitro</i>. However, compared with the parental MeWo cell line, significantly higher concentrations of proteasome inhibitor are required to reduce cell viability of MeWo<sub>cis1</sub> cells. Moreover, whereas proteasome activity was inhibited to the same extent in both cell lines, IκBα degradation and nuclear factor-κB (NF-κB) activation in MeWo<sub>cis1</sub> cells was proteasome inhibitor independent but essentially calpain inhibitor sensitive. In support, a calpain-specific inhibitor impaired NF-κB activation in MeWo<sub>cis1</sub> cells. Here, we show that cisplatin resistance in MeWo<sub>cis1</sub> is accompanied by a change in the NF-κB activation pathway in favor of calpain-mediated IκBα degradation. Furthermore, combined exposure to proteasome and calpain inhibitor resulted in additive effects and a strongly reduced cell viability of MeWo<sub>cis1</sub> 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)</p></div>