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

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, IκBα degradation and nuclear factor-κB (NF-κB) activation in MeWo_cis1 cells was proteasome inhibitor independent but essentially calpain inhibitor sensitive. In support, a calpain-specific inhibitor impaired NF-κB activation in MeWo_cis1 cells. Here, we show that cisplatin resistance in MeWo_cis1 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_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)