title: Drug combinations with proteasome inhibitors in antitumor therapy.
abstract: The proteasome has been regarded as a major target for antitumor therapy in selected tumor types (i.e., multiple myeloma). Available evidence suggests that targeting the proteasome with selective compounds can represent an excellent approach for modulating the response to antitumor agents including both conventional cytotoxic agents and target-specific agents. In fact, promising drug interaction data showing synergistic effects have been reported in cellular studies, both in multiple myeloma and in solid tumors. The mechanistic bases of improved efficacy of drug combinations including bortezomib or other proteasome inhibitors and conventional cytotoxic agents have been in part unravelled and involve the capability of proteasome inhibitors to interfere with the stability of the targets of cytotoxic agents (e.g., topoisomerase inhibitors) as well as with cellular protective pathways (e.g., DNA repair and NF-kB-regulated gene expression). Moreover, the synergistic interaction of proteasome inhibitors and target-specific agents implicates a variety of mechanisms linked to the specific target (e.g., histone deacetylase) modulated by the tailored drug used in combination with the proteasome inhibitor. Several clinical studies are ongoing in an attempt to define drug combination approaches that enhance the efficacy of antitumor treatments. Considering the fast moving field of preclinical research regarding proteasome inhibition, a major contribution to the understanding of the bases of tumor response to treatment with proteasome inhibitors is expected.
authors.affiliation: Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCSS Istituto Nazionaledei Tumori, 20133 Milan, Italy. laura.gatti@istitutotumori.mi.it
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D059003:Topoisomerase Inhibitors / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D059003:Topoisomerase Inhibitors; D046988:Proteasome Endopeptidase Complex