College of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada.
Cardiovasc Toxicol. 2018 Dec;18(6):557-568. doi: 10.1007/s12012-018-9468-9.
The proteasome inhibitors bortezomib, carfilzomib, and ixazomib, which are used in the treatment of multiple myeloma have greatly improved response rates. Several other proteasome inhibitors, including delanzomib and oprozomib, are in clinical trials. Carfilzomib and oprozomib are epoxyketones that form an irreversible bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. Several of the proteasome inhibitors have been shown to exhibit specific cardiac toxicities. A primary neonatal rat myocyte model was used to study the relative myocyte-damaging effects of five proteasome inhibitors with a view to identifying potential class differences and the effect of inhibitor binding kinetics. Bortezomib was shown to induce the most myocyte damage followed by delanzomib, ixazomib, oprozomib, and carfilzomib. The sensitivity of myocytes to proteasome inhibitors, which contain high levels of chymotrypsin-like proteasomal activity, may be due to inhibition of proteasomal-dependent ongoing sarcomeric protein turnover. All inhibitors inhibited the chymotrypsin-like proteasomal activity of myocyte lysate in the low nanomolar concentration range and exhibited time-dependent inhibition kinetics characteristic of slow-binding inhibitors. Progress curve analysis of the inhibitor concentration dependence of the slow-binding kinetics was used to measure second-order "on" rate constants for binding. The second-order rate constants varied by 90-fold, with ixazomib reacting the fastest, and oprozomib the slowest. As a group, the boronic acid drugs were more damaging to myocytes than the epoxyketone drugs. Overall, inhibitor-induced myocyte damage was positively, but not significantly, correlated with their second-order rate constants.
蛋白酶体抑制剂硼替佐米、卡非佐米和伊沙佐米用于治疗多发性骨髓瘤，大大提高了缓解率。其他几种蛋白酶体抑制剂，包括丹那佐米和奥普佐米，正在临床试验中。卡非佐米和奥普佐米是环氧酮，与 20S 蛋白酶体形成不可逆的键，而硼替佐米、伊沙佐米和丹那佐米是硼酸，形成缓慢可逆的加合物。几种蛋白酶体抑制剂已被证明具有特定的心脏毒性。使用原代新生大鼠心肌细胞模型研究了五种蛋白酶体抑制剂对心肌细胞的相对损伤作用，以期确定潜在的类差异和抑制剂结合动力学的影响。结果显示，硼替佐米诱导的心肌细胞损伤最严重，其次是丹那佐米、伊沙佐米、奥普佐米和卡非佐米。含有高水平糜蛋白酶样蛋白酶体活性的蛋白酶体抑制剂对心肌细胞的敏感性可能是由于抑制蛋白酶体依赖性肌节蛋白不断更新。所有抑制剂均在纳摩尔浓度范围内抑制心肌细胞裂解物的糜蛋白酶样蛋白酶体活性，并表现出特征性的缓慢结合抑制剂的时间依赖性抑制动力学。抑制剂浓度对缓慢结合动力学的进展曲线分析用于测量结合的二级“on”速率常数。二级速率常数相差 90 倍，伊沙佐米反应最快，奥普佐米反应最慢。作为一个整体，硼酸类药物比环氧酮类药物对心肌细胞的损伤更大。总的来说，抑制剂诱导的心肌细胞损伤与它们的二级速率常数呈正相关，但无显著相关性。
