Škrott Zdeněk, Cvek Boris
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, 78371 Olomouc, Czech Republic.
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, 78371 Olomouc, Czech Republic.
Crit Rev Oncol Hematol. 2014 Nov;92(2):61-70. doi: 10.1016/j.critrevonc.2014.05.003. Epub 2014 May 10.
Since their introduction to the clinic 10 years ago, proteasome inhibitors have become the cornerstone of anti-multiple myeloma therapy. Despite significant progress in understanding the consequences of proteasome inhibition, the unique activity of bortezomib is still unclear. Disappointing results from clinical trials with bortezomib in other malignancies raise the question of what makes multiple myeloma so sensitive to proteasome inhibition. Successful administration of bortezomib in various immunological disorders that exhibit high antibody production suggests that the balance between protein synthesis and degradation is a key determinant of sensitivity to proteasome inhibition because a high rate of protein production is a shared characteristic in plasma and myeloma cells. Initial or acquired resistance to bortezomib remains a major obstacle in the clinic as in vitro data from cell lines suggest a key role for the β5 subunit mutation in resistance; however the mutation was not found in patient samples. Recent studies indicate the importance of selecting for a subpopulation of cells that produce lower amounts of paraprotein during bortezomib therapy.
自10年前蛋白酶体抑制剂引入临床以来，它们已成为抗多发性骨髓瘤治疗的基石。尽管在理解蛋白酶体抑制的后果方面取得了重大进展，但硼替佐米的独特活性仍不清楚。硼替佐米在其他恶性肿瘤的临床试验中令人失望的结果，引发了关于是什么使得多发性骨髓瘤对蛋白酶体抑制如此敏感的问题。硼替佐米在各种表现出高抗体产生的免疫性疾病中的成功应用表明，蛋白质合成与降解之间的平衡是对蛋白酶体抑制敏感性的关键决定因素，因为高蛋白质产生率是浆细胞和骨髓瘤细胞的共同特征。硼替佐米的初始或获得性耐药仍然是临床上的一个主要障碍，因为来自细胞系的体外数据表明β5亚基突变在耐药中起关键作用；然而，在患者样本中未发现该突变。最近的研究表明，在硼替佐米治疗期间选择产生较低量副蛋白的细胞亚群很重要。
