Rationale for Combining the Proteasome Inhibitor Bortezomib with Cisplatin

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