Inhibition of different steps of the ubiquitin system by cisplatin and aclarubicin

• Published in: Biochimica et Biophysica Acta (BBA) - General Subjects Vol. 1117; no. 2; pp. 131 - 135
• Main Authors: Isoe, Toshiyuki, Naito, Mikihiko, Shirai, Akio, Hirai, Reiko, Tsuruo, Takashi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.09.1992; Elsevier BV; Elsevier
• Subjects: Aclarubicin; Aclarubicin - pharmacology; Adenosine Triphosphate; Adenosine Triphosphate - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Cancer chemotherapy; Cisplatin; Cisplatin - pharmacology; Drug resistance; Endopeptidases; Endopeptidases - metabolism; General aspects; Ligases; Ligases - antagonists & inhibitors; Medical sciences; Mitomycin; Mitomycin - pharmacology; Pharmacology. Drug treatments; Rabbits; Reticulocytes; Reticulocytes - drug effects; Reticulocytes - metabolism; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Protein Ligases; Ubiquitins; Ubiquitins - antagonists & inhibitors; Ubiquitins - metabolism; Ubiquitins - pharmacology; Ubiquitin; Cancer chemotherapy; m-AMSA4′-(9-acridinyl-amino)methansulfon- m-anisidide; Aclarubicin; Drug resistance; E1; Cisplatin; ACR, aclarubicin; Antineoplastic agent; Animal model; Vertebrata; Chemotherapy; Mammalia; Rabbit; Reticulocyte; Lagomorpha; Mechanism of action; Biological activity; Dose activity relation
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/0304-4165(92)90070-B

Ubiquitin is involved in such fundamental cellular processes as cell cycle control, DNA repair, protein degradation and stress responses. We previously reported that cisplatin could inhibit the ubiquitin-ATP-dependent proteolysis and ubiquitination. We further investigated the effect of various antitumor agents on the ubiquitin system and found that aclarubicin (ACR) inhibits the ubiquitin-ATP-dependent proteolysis but not the ubiquitination process. We found that ACR as well as cisplatin inhibited the ubiquitin-ATP-dependent proteolytic activity of rabbit reticulocytes. The IC 50 values of these agents were 52 and 90 μM, respectively. Although cisplatin inhibits the conjugation of ubiquitin to proteins through the inhibition of a ubiquitin-activating enzyme, ACR, at 120 μM, does not. Thus, the antitumor agents affecting the ubiquitin system could be classified into two groups; one is represented by cisplatin, which inhibits the ubiquitination of the proteins, and the other is ACR, which does not inhibit the ubiquitination but does inhibit the ubiquitin-ATP-dependent proteolysis. Mitomycin C belongs to the latter group.