Chauhan Dharminder, Bianchi Giada, Anderson Kenneth C
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
BMC Biochem. 2008 Oct 21;9 Suppl 1(Suppl 1):S1. doi: 10.1186/1471-2091-9-S1-S1.
The coordinated regulation of cellular protein synthesis and degradation is essential for normal cellular functioning. The ubiquitin proteasome system mediates the intracellular protein degradation that is required for normal cellular homeostasis. The 26S proteasome is a multi-enzyme protease that degrades redundant proteins; conversely, inhibition of proteasomal degradation results in intracellular aggregation of unwanted proteins and cell death. This observation led to the development of proteasome inhibitors as therapeutics for use in cancer. The clinical applicability of targeting proteasomes is exemplified by the recent FDA approval of the first proteasome inhibitor, bortezomib, for the treatment of relapsed/refractory multiple myeloma. Although bortezomib represents a major advance in the treatment of this disease, it can be associated with toxicity and the development of drug resistance. Importantly, extensive preclinical studies suggest that combination therapies can both circumvent drug resistance and reduce toxicity. In addition, promising novel proteasome inhibitors, which are distinct from bortezomib, and exhibit equipotent anti-multiple myeloma activities, are undergoing clinical evaluation in order to improve patient outcome in multiple myeloma. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
细胞蛋白质合成与降解的协调调控对于细胞的正常功能至关重要。泛素蛋白酶体系统介导正常细胞稳态所需的细胞内蛋白质降解。26S蛋白酶体是一种多酶蛋白酶，可降解多余的蛋白质；相反，蛋白酶体降解的抑制会导致不需要的蛋白质在细胞内聚集并导致细胞死亡。这一观察结果促使蛋白酶体抑制剂作为癌症治疗药物得以开发。靶向蛋白酶体的临床适用性体现在美国食品药品监督管理局（FDA）最近批准了首个蛋白酶体抑制剂硼替佐米用于治疗复发/难治性多发性骨髓瘤。尽管硼替佐米代表了该疾病治疗的重大进展，但它可能与毒性和耐药性的产生有关。重要的是，广泛的临床前研究表明，联合疗法既能规避耐药性又能降低毒性。此外，与硼替佐米不同且具有同等抗多发性骨髓瘤活性的新型蛋白酶体抑制剂正在进行临床评估，以改善多发性骨髓瘤患者的治疗效果。发表历史：转载自Current BioData的靶向蛋白质数据库（TPdb；http://www.targetedproteinsdb.com）。
