Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity.
Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity.
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DOI：
10.1038/srep28861
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发表时间：
2016-06-28
影响因子：
4.6
通讯作者：
Hoke A
中科院分区：
文献类型：
--
作者：
Zhu J;Carozzi VA;Reed N;Mi R;Marmiroli P;Cavaletti G;Hoke A
乙氧喹最近被确定为一种抗毒性神经病的神经保护化合物，并在体内证明了对紫杉醇诱导的神经毒性的有效性。在本研究中，我们检测了乙氧喹在化疗诱导的周围神经病变啮齿动物模型中对顺铂神经毒性的预防作用，并探讨了其作用机制。乙氧喹对感觉神经元细胞系和原代大鼠背根神经节神经元的神经毒性有抑制作用。在体内，长期联合使用乙氧喹部分消除了顺铂诱导的行为、电生理和形态异常。此外，在体外和体内实验中，乙氧喹不干扰顺铂诱导卵巢癌细胞系肿瘤细胞死亡的能力。最后，在体外实验中，当与顺铂共同给药时，甲氧基醌降低了伴侣蛋白热休克蛋白90 （Hsp90）的两种客户蛋白（SF3B2和ataxin-2）的水平。这些结果表明，乙氧喹的神经保护作用是通过Hsp90的这两个客户蛋白介导的。事实上，降低组织培养神经元中SF3B2的水平对顺铂的神经毒性是有效的。这些发现表明，乙氧喹或其他化合物可以抑制Hsp90的伴侣活性并降低其客户蛋白水平，SF3B2可能被开发为一种辅助治疗，以防止顺铂化疗方案中的神经毒性。
Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin’s ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols.