Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons.
Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons.
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DOI：
10.1016/j.neuro.2013.09.001
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发表时间：
2013-12
期刊：
影响因子：
3.4
通讯作者：
Windebank, Anthony J.
中科院分区：
文献类型：
--
作者：
Staff, Nathan P.;Podratz, Jewel L.;Grassner, Lukas;Bader, Miranda;Paz, Justin;Knight, Andrew M.;Loprinzi, Charles L.;Trushina, Eugenia;Windebank, Anthony J.
关键词：
硼替佐米是一类较新的化疗药物的一部分，其作用机制是抑制蛋白酶体-泛素化系统。硼替佐米主要用于多发性骨髓瘤，在大约30%的患者中引起感觉为主的轴突周围神经病变。硼替佐米诱导的周围神经病变（BIPN）尚无确定的有效预防药物，BIPN的分子机制尚不清楚。我们已经建立了一个在体外模型的BIPN使用大鼠背根神经节神经元培养。在临床相关剂量下，硼替佐米产生感觉轴突病，如整个外植体生长和细胞存活测定所证明。这种感觉轴突病与微管蛋白的改变有关，并导致体细胞微管蛋白的积累而不改变微管超微结构。此外，我们观察到在硼替佐米处理的DRG神经元中聚合微管蛋白的比例增加，但不是总微管蛋白或乙酰化微管蛋白。lactacystin是一种不相关的蛋白酶体抑制剂，也有类似的发现，这表明蛋白酶体抑制对背根神经节神经元有类效应。最后，硼替佐米诱导的线粒体轴突运输以时间依赖性方式发生变化。总之，我们已经开发了一种体外模型的BIPN，概括了临床感觉轴突病，该模型表明，硼替佐米诱导微管和轴突运输的改变。该模型可用于今后BIPN及其防治的机理研究。
Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically–relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.
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DOI：
10.1016/j.jpain.2011.04.008
发表时间：
2011-09
期刊：
The journal of pain
影响因子：
--
作者：
Boyette-Davis JA;Cata JP;Zhang H;Driver LC;Wendelschafer-Crabb G;Kennedy WR;Dougherty PM
通讯作者：
Dougherty PM
影响因子：
6.1
作者：
Podratz, Jewel L.;Knight, Andrew M.;Ta, Lauren E.;Staff, Nathan P.;Gass, Jennifer M.;Genelin, Konstantin;Schlattau, Alexander;Lathroum, Liselle;Windebank, Anthony J.
通讯作者：
Windebank, Anthony J.
影响因子：
11.4
作者：
TRAENCKNER, EBM;WILK, S;BAEUERLE, PA
通讯作者：
BAEUERLE, PA
影响因子：
3.6
作者：
Meregalli, Cristina;Canta, Annalisa;Cavaletti, Guido
通讯作者：
Cavaletti, Guido
影响因子：
4.3
作者：
Poruchynsky, Marianne S.;Sackett, Dan L.;Fojo, Tito
通讯作者：
Fojo, Tito