Title:Drug Combinations with Proteasome Inhibitors in Antitumor Therapy
Volume: 19
Issue: 22
Author(s): Laura Gatti, Valentina Zuco, Nadia Zaffaroni and Paola Perego
Affiliation:
Keywords:
Proteasome, combination treatment, cytotoxic agents, target-specific agents.
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.
