Abstract:
Carfilzomib (CFZ) is the second-generation proteasome inhibitor that is approved by Food and Drug Administration (FDA) of USA for the treatment of relapsed and refractory multiple myeloma. Although the preclinical and clinical efficacy of CFZ is obvious, the mechanism by which CFZ leads to cell death has not been fully elucidated. Since CFZ primarily functions as a proteasome inhibitor, profiling CFZ-induced changes in protein turnover at the systematic level is sufficient and necessary. In this study, we characterize the effects of CFZ on the stability of 15,000 human proteins using Protein Turnover Assay (ProTA). CFZ affects fundamental cellular glycolysis, nitric oxide production and proteasome subunit homeostasis in multiple myeloma cells. In addition, LY294002 or KU-0063794 has synergistic effects with CFZ in multiple myeloma treatment. A profound understanding of how cells respond to chemotherapeutic agents provides insights into the basic mechanism of drug function and the rationale for CFZ combination therapy.
摘要:
卡非佐米(CFZ)是美国食品药品监督管理局(FDA)批准的第二代蛋白酶体抑制剂,用于治疗复发和难治性多发性骨髓瘤。虽然CFZ的临床前和临床疗效明显,CFZ导致细胞死亡的机制尚未完全阐明。由于CFZ主要作为蛋白酶体抑制剂,在系统水平上分析CFZ诱导的蛋白质周转变化是足够和必要的。在这项研究中,我们使用蛋白质周转分析(ProTA)表征了CFZ对15,000种人类蛋白质的稳定性的影响。CFZ影响基本细胞糖酵解,多发性骨髓瘤细胞中一氧化氮的产生和蛋白酶体亚基稳态。此外,LY294002或KU-0063794在多发性骨髓瘤治疗中与CFZ具有协同作用。对细胞对化学治疗剂的反应的深刻理解提供了对药物功能的基本机制和CFZ联合治疗原理的见解。