Mujtaba Taskeen, Dou Q Ping
Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Discov Med. 2011 Dec;12(67):471-80.
The ubiquitin-proteasome pathway regulates many basic cellular processes and has been proven to be a promising target for cancer therapy. Bortezomib is the first U.S. Food and Drug Administration (FDA) approved proteasome inhibitor used in the treatment of newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and mantle cell lymphoma. The anti-cancer mechanisms of bortezomib elucidated by preclinical studies include: upregulation of proapoptotic proteins (e.g., Noxa, IκB), inhibition of NFκB and its anti-apoptotic target genes, suppression of several anti-apoptotic proteins (e.g., Bcl-XL, Bcl-2, and STAT-3), down-regulation of expression of several proteins involved in DNA repair pathways, and induction of endoplasmic reticulum (ER) stress and pro-apoptotic Unfolded Protein Response (UPR). Bortezomib has potent chemo-/radio-sensitizing effects and can overcome traditional drug resistance in tumors when used in combination with potential chemotherapies. Although bortezomib has been successful in improving clinical outcomes when used in hematological malignancies, relapse may occur in those patients who responded initially. Furthermore, some cytotoxicities (such as peripheral neuropathy) were found to be associated with bortezomib treatment. These observations have encouraged researchers to search for the next generation proteasome inhibitors (including carfilzomib and marizomib) that could overcome bortezomib resistance and have improved properties, reduced toxicities, and broader anticancer activities, based on the lessons learned from the mechanisms and use of bortezomib. This review summarizes the current status of bortezomib as well as several other proteasome inhibitors that are currently under clinical and preclinical investigation.
泛素-蛋白酶体途径调节许多基本的细胞过程，并且已被证明是癌症治疗的一个有前景的靶点。硼替佐米是美国食品药品监督管理局（FDA）批准的首个用于治疗新诊断的多发性骨髓瘤、复发/难治性多发性骨髓瘤和套细胞淋巴瘤的蛋白酶体抑制剂。临床前研究阐明的硼替佐米的抗癌机制包括：上调促凋亡蛋白（如Noxa、IκB），抑制NFκB及其抗凋亡靶基因，抑制几种抗凋亡蛋白（如Bcl-XL、Bcl-2和STAT-3），下调参与DNA修复途径的几种蛋白的表达，以及诱导内质网（ER）应激和促凋亡的未折叠蛋白反应（UPR）。硼替佐米具有强大的化疗/放疗增敏作用，与潜在的化疗药物联合使用时可克服肿瘤中的传统耐药性。尽管硼替佐米用于血液系统恶性肿瘤时已成功改善了临床结果，但最初有反应的患者可能会复发。此外，发现一些细胞毒性（如周围神经病变）与硼替佐米治疗有关。基于从硼替佐米的作用机制和使用中吸取的经验教训，这些观察结果促使研究人员寻找下一代蛋白酶体抑制剂（包括卡非佐米和马立佐米），它们可以克服硼替佐米耐药性，具有更好的特性、更低的毒性和更广泛的抗癌活性。本综述总结了硼替佐米以及目前正在进行临床和临床前研究的其他几种蛋白酶体抑制剂的现状。
