Ishii Yuki, Waxman Samuel, Germain Doris
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Anticancer Agents Med Chem. 2007 May;7(3):359-65. doi: 10.2174/187152007780618180.
The ubiquitin-proteasome pathway plays a central role in the degradation of proteins involved in several pathways including the cell cycle, cellular proliferation and apoptosis. Bortezomib is the first proteasome inhibitor to enter clinical use, and received approval by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma, therefore validating inhibition of the proteasome as an anticancer target. The approval of Bortezomib was based on a large, international, multicenter phase III trial showing its efficacy and safety compared with conventional therapy. Preclinical data also demonstrates the synergistic effect of bortezomib with other chemotherapeutic agents and its ability to overcome drug resistance. Since then several other proteasome inhibitors have been developed. The anti-tumor activities of bortezomib have been attributed to its effect on pro-apoptotic pathways including the inhibition of NF-kappaB and induction of endoplasmic reticulum stress. However, the molecular mechanisms are not fully understood. In this review, we will summarize the molecular mechanism of apoptosis by bortezomib.
泛素-蛋白酶体途径在参与包括细胞周期、细胞增殖和凋亡在内的多种途径的蛋白质降解中起着核心作用。硼替佐米是首个进入临床应用的蛋白酶体抑制剂，并获得了美国食品药品监督管理局（FDA）批准用于治疗多发性骨髓瘤患者，从而证实了蛋白酶体抑制作为抗癌靶点的有效性。硼替佐米的获批基于一项大型国际多中心III期试验，该试验显示了其与传统疗法相比的疗效和安全性。临床前数据还证明了硼替佐米与其他化疗药物的协同作用及其克服耐药性的能力。从那时起，又开发了其他几种蛋白酶体抑制剂。硼替佐米的抗肿瘤活性归因于其对促凋亡途径的作用，包括抑制核因子κB和诱导内质网应激。然而，其分子机制尚未完全明确。在本综述中，我们将总结硼替佐米诱导凋亡的分子机制。
