Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCSS Istituto Nazionaledei Tumori, 20133 Milan, Italy.
Curr Pharm Des. 2013;19(22):4094-114. doi: 10.2174/1381612811319220015.
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.
蛋白酶体已被视为某些肿瘤类型（如多发性骨髓瘤）的抗肿瘤治疗的主要靶点。现有证据表明，用选择性化合物靶向蛋白酶体可能是一种调节抗肿瘤药物反应的极好方法，包括常规细胞毒性药物和靶向特定药物。事实上，在细胞研究中已经报道了具有协同作用的有希望的药物相互作用数据，无论是在多发性骨髓瘤还是实体瘤中。包括硼替佐米或其他蛋白酶体抑制剂和常规细胞毒性药物在内的药物组合疗效提高的机制基础部分已经阐明，这涉及蛋白酶体抑制剂干扰细胞毒性药物（如拓扑异构酶抑制剂）的靶点稳定性以及细胞保护途径（如 DNA 修复和 NF-κB 调节的基因表达）的能力。此外，蛋白酶体抑制剂和靶向药物的协同相互作用涉及与特定靶标（如组蛋白去乙酰化酶）相关的多种机制，这些靶标由与蛋白酶体抑制剂联合使用的定制药物调节。正在进行几项临床研究，试图确定增强抗肿瘤治疗效果的药物联合方法。考虑到针对蛋白酶体抑制的临床前研究领域的快速发展，预计这将对理解肿瘤对蛋白酶体抑制剂治疗的反应基础做出重大贡献。
