Inhibition of ubiquitin-ATP-dependent proteolysis and ubiquitination by cisplatin.

We tested the inhibitory activity of various antitumor agents on the ubiquitin-ATP-dependent proteolytic activity in rabbit reticulocyte lysates. We found that cisplatin, 4'-(9-acridinyl-amino) methanesulfon-m-anisidide (m-AMSA) and mitomycin C inhibited the ubiquitin-ATP-dependent proteolysis. IC50 values (50% inhibition concentrations) of these antitumor agents were 90, 210 and above 290 microM, respectively. Furthermore, cisplatin was found to inhibit the conjugation of ubiquitin to endogenous proteins in fraction II at 100 and 330 microM. These results suggest that cisplatin interacts with the enzyme(s) involved in ubiquitin conjugation and thus inhibits the ubiquitin-ATP-dependent protein degradation. We assume that the agents that can affect the ubiquitin system might be useful for the treatment of tumors and that the ubiquitin system could be a new target for cancer chemotherapy.