Apoptosis meets proteasome, an invaluable therapeutic target of anticancer drugs.
This report reviews the current status of extensive efforts directed towards the interpretation of crosstalk between apoptosis and proteasome to understanding the molecular mechanism of anticancer agents targeting proteasome, with particular focus on MG132 and PS-341. The discovery that all cancer cells have retained the apoptotic death program has offered to the researchers new biochemical targets to design anticancer drugs. Moreover, the demonstration that proteasome inhibition induces apoptosis and sensitizes cancer cells to traditional tumoricidal agents has proposed the proteasome as an attractive target for development of new anticancer drugs. Since then, a number of both naturally occurring and synthetic inhibitors of the proteasome have been identified. The best characterized and most widely used inhibitors of the proteasome are the peptide aldehydes; among these MG132, due to its broad spectrum of action, low cost and rapid reversibility of action, still remains the first choice to study proteasome function in cell and tissue cultures. Recently, a very potent new class of selective and reversible proteasome inhibitors which contains an inhibitory boronate group has been described. PS-341 represent the first of this promising class of agents that could have application in cancer therapy and it is the only that has progressed to clinical trials.
Giuliano
Michela
M
Dipartimento di Biologia Cellulare e dello Sviluppo, Sezione di Biochimica, Policlinico, Università di Palermo, Italy.
D'Anneo
Antonella
A
De Blasio
Anna
A
Vento
Renza
R
Tesoriere
Giovanni
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003546:Cysteine Endopeptidases; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D007976:Leupeptins; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde