Department of Drug Safety Evaluation, Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA.
Vet Pathol. 2010 Mar;47(2):358-67. doi: 10.1177/0300985809358423. Epub 2010 Feb 1.
Proteasome inhibitor therapeutics (PITs) have the potential to cause peripheral neuropathy. In a mouse model of PIT-induced peripheral neuropathy, the authors demonstrated that ubiquitin-positive multifocal protein aggregates with nuclear displacement appear in dorsal root ganglion cells of animals that subsequently develop nerve injuries. This peripheral-nerve effect in nonclinical models has generally been recognized as the correlate of grade 3 neuropathy in clinical testing. In differentiated PC12 cells, the authors demonstrated perturbations correlative with the development of neuropathy in vivo, including ubiquitinated protein aggregate (UPA) formation and/or nuclear displacement associated with the degree of proteasome inhibition. They compared 7 proteasome inhibitors of 3 chemical scaffolds (peptide boronate, peptide epoxyketone, and lactacystin analog) to determine if PIT-induced peripheral neuropathy is modulated by inhibition of the proteasome (ie, a mechanism-based effect) or due to effects independent of proteasome inhibition (ie, an off target or chemical-structure-based effect). The appearance of UPAs was assayed at IC(90) +/- 5% (90% inhibition concentration +/- 5%) for 20S proteasome inhibition. Results show that each of the investigated proteasome inhibitors induced identical proteasome-inhibitor-specific ubiquitin-positive immunostaining and nuclear displacement in PC12 cells. Other agents--such as paclitaxel, cisplatin, and thalidomide, which cause neuropathy by other mechanisms--did not cause UPAs or nuclear displacement, demonstrating that the effect was specific to proteasome inhibitors. In conclusion, PIT-induced neuronal cell UPA formation and nuclear displacement are mechanism based and independent of the proteasome inhibitor scaffold. These data indicate that attempts to modulate the neuropathy associated with PIT may not benefit from changing scaffolds.
蛋白酶体抑制剂治疗（PIT）有可能引起周围神经病。在 PIT 诱导的周围神经病的小鼠模型中，作者证明，在随后发生神经损伤的动物的背根神经节细胞中，出现了带有核移位的泛素阳性多灶性蛋白聚集物。这种非临床模型中的周围神经效应通常被认为与临床测试中 3 级神经病相对应。在分化的 PC12 细胞中，作者证明了与体内神经病发展相关的扰动，包括泛素化蛋白聚集物（UPA）的形成和/或与蛋白酶体抑制程度相关的核移位。他们比较了 3 种化学支架（肽硼酸酯、肽环氧化物酮和乳酰环胞素类似物）的 7 种蛋白酶体抑制剂，以确定 PIT 诱导的周围神经病是否受蛋白酶体抑制的调节（即基于机制的效应）或由于与蛋白酶体抑制无关的效应（即非靶点或基于化学结构的效应）。在 20S 蛋白酶体抑制的 IC（90）+/-5%（90%抑制浓度+/-5%）处测定 UPA 的出现。结果表明，所研究的每种蛋白酶体抑制剂都在 PC12 细胞中诱导了相同的蛋白酶体抑制剂特异性泛素阳性免疫染色和核移位。其他药物（如紫杉醇、顺铂和沙利度胺，它们通过其他机制引起神经病）不会引起 UPA 或核移位，表明该效应是特异性的蛋白酶体抑制剂。总之，PIT 诱导的神经元细胞 UPA 形成和核移位是基于机制的，与蛋白酶体抑制剂支架无关。这些数据表明，试图调节与 PIT 相关的神经病可能不会受益于改变支架。
