Rationale for Combining the Proteasome Inhibitor Bortezomib with Cisplatin

Abstract

The proteasome inhibitor bortezomib is currently undergoing advanced clinical evaluation as a new anticancer drug. Found to be highly effective against multiple myeloma, bortezomib will soon be tested with first-line anticancer drugs against a broad range of human malignancies, including solid tumors. Preclinical studies indicate that proteasome inhibition potentiates the activity of several conventional antitumor agents. Here we offer a rationale for combining bortezomib with the DNA-targeting drug cisplatin. First, the removal of cisplatin covalent adducts from DNA by nucleotide excision repair is greatly diminished by proteasome inhibition, and second, induction of the crucial DNA-repair enzyme excision repair cross-complementation group 1 (ERCC- 1) by cisplatin is prevented by proteasome inhibitor pretreatment. Both of these pharmacologic events have been linked to proteasome inhibitor-caused de-ubiquitination of nucleosomal core histones H2A and H2B, which is associated with chromatin condensation and transcriptional inhibition. Thus, bortezomib has the potential to simultaneously enhance the anticancer efficacy of cisplatin and to prevent the emergence of ERCC- 1-dependent cisplatin resistance.