Cisplatin resistance in human ovarian cancer cells and its modulation by signaling pathway- and nuclear transcription factor NF kappa-B inhibition

By NF-κB activation inhibition, proteasome inhibition and inhibition of proteasome ubiquitination, in chemosensitive and cisplatin-resistant human ovarian carcinoma cells, was gained a more precise insight into the molecular mechanism(s) of a complex intracellular apoptosis- and/or signaling network that ultimately regulates gene expression in response to NF-κB- or proteasome activity/ubiquitination inhibition asociated with apoptosis and resistance. It was shown that in these cells cisplatin resistance is associated not only with alterations in proteome signaling molecules associated with apoptosis, but also with the changes in the cell lysosomal compartment linked with the activity of lysosomal transporters responsible for cisplatin efflux. It was further determined, that cisplatin export was not modulated by the single inhibition of NF-κB transcriptional akctivation (i.e. by inhibition of interaction between RNA polymerase and a particular promoter through interactions with subunits of the RNA polymerase), or by inhibition of proteasomal ubiquitination, however it was inhibited by proteasomal activity inhibition. These results confirmed the effectiveness of a catalytic activity of proteasome inhibition in the modulation of cisplatin resistance in experimental chemotherapy of human cancer cells and the possibility of clinical application of proteasome inhibition in the therapy of some human cancers.