Department of Surgery and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, CA 90095, USA.
Am J Cancer Res. 2011;1(7):913-24. Epub 2011 Aug 23.
Protein degradation by proteasome is essential to the regulation of important cellular functions including cell cycle progression, proliferation, differentiation and apoptosis. Abnormal proteasomal degradation of key regulatory proteins perturbs the normal dynamics of these cellular processes culminating in uncontrolled cell cycle progression and decreased apoptosis leading to the characteristic cancer cell phenotype. Proteasome inhibitors are a novel group of therapeutic agents designed to oppose the increased proteasomal degradation observed in various cancers while restoring key cellular functions such as apoptosis, cell cycle progression, and the inhibition of angiogenesis. Several proteasome inhibitors have been evaluated in pre- and clinical studies for their potential usage in clinical oncology. Bortezomib (Velcade, PS-341) is the first Food and Drug Administration-approved proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib's ability to preferentially induce toxicity and cell death in tumor cells while rendering healthy cells unaffected makes it a powerful therapeutic agent and has extended its use in other types of malignancies. The ability of bortezomib and other proteasome inhibitors to synergize with conventional therapies in killing tumors in various in vitro and in vivo models makes this class of drugs a powerful tool in overcoming acquired and inherent resistance observed in many cancers. This is achieved through modulation of aberrant cellular survival signal transduction pathways and their downstream anti-apoptotic gene products. This review will discuss the anti-neoplastic effects of various proteasome inhibitors in a variety of cancers with a special emphasis on bortezomib, its mechanism of action and role in cancer therapy. We further discuss the potential use of bortezomib in the treatment of metastatic melanoma.
蛋白酶体介导的蛋白质降解对于调节细胞的重要功能是必需的，包括细胞周期进程、增殖、分化和凋亡。关键调节蛋白的异常蛋白酶体降解扰乱了这些细胞过程的正常动态，导致失控的细胞周期进程和凋亡减少，从而导致典型的癌细胞表型。蛋白酶体抑制剂是一类新型的治疗剂，旨在对抗各种癌症中观察到的蛋白酶体降解增加，同时恢复细胞凋亡、细胞周期进程和血管生成抑制等关键细胞功能。已经在临床前和临床研究中评估了几种蛋白酶体抑制剂，以评估它们在肿瘤学中的潜在用途。硼替佐米（Velcade，PS-341）是第一个获得美国食品和药物管理局批准的蛋白酶体抑制剂，用于治疗多发性骨髓瘤和套细胞淋巴瘤。硼替佐米能够优先诱导肿瘤细胞毒性和细胞死亡，而对健康细胞没有影响，这使其成为一种强大的治疗剂，并已将其用途扩展到其他类型的恶性肿瘤。硼替佐米和其他蛋白酶体抑制剂在各种体外和体内模型中与常规治疗协同杀伤肿瘤的能力使这类药物成为克服许多癌症中观察到的获得性和固有耐药性的有力工具。这是通过调节异常的细胞存活信号转导途径及其下游的抗凋亡基因产物来实现的。本文将讨论各种蛋白酶体抑制剂在多种癌症中的抗肿瘤作用，特别强调硼替佐米，其作用机制及其在癌症治疗中的作用。我们进一步讨论了硼替佐米在治疗转移性黑色素瘤中的潜在用途。
