Oxaliplatin-induced blood brain barrier loosening: a new point of view on chemotherapy-induced neurotoxicity.
Oxaliplatin-induced blood brain barrier loosening: a new point of view on chemotherapy-induced neurotoxicity.
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DOI：
10.18632/oncotarget.25193
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发表时间：
2018-05-04
期刊：
影响因子：
--
通讯作者：
Pacini A
中科院分区：
文献类型：
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作者：
Branca JJV;Maresca M;Morucci G;Becatti M;Paternostro F;Gulisano M;Ghelardini C;Salvemini D;Di Cesare Mannelli L;Pacini A
奥沙利铂是治疗晚期转移性结直肠癌的关键药物。尽管奥沙利铂治疗对肿瘤减少有有益作用，但最普遍的副作用是化疗引起的神经病变，经常迫使患者停止治疗。事实上，除了对周围神经的直接损伤外，化疗相关的神经毒性还涉及中枢神经系统（CNS），如慢性疼痛和认知障碍（也称为化学脑），这是一种新描述的药理学副作用。血脑屏障（BBB）的存在有助于防止药物进入中枢神经系统；在这里，我们测试了奥沙利铂可能进入血脑屏障血管内皮细胞并触发信号通路，诱导紧密连接的解体，这是血脑屏障完整性的关键组成部分。通过使用大鼠脑内皮细胞系（RBE4），我们研究了奥沙利铂进入细胞后的信号通路。我们发现给药10 μM奥沙利铂8和16小时可诱导紧密连接（TJs）蛋白zoonula occluden -1 （ZO-1）和F-actin的改变，从而突出血脑屏障的改变。此外，我们报道了细胞内奥沙利铂迅速诱导活性氧和内质网应激水平升高，通过评估葡萄糖调节蛋白GRP78表达水平来评估。这些事件伴随着caspase-3的激活，导致细胞外ATP释放。这些发现提示了奥沙利铂毒性的一种可能的新作用机制，至少在一定程度上可以解释化疗相关的中心效应。
Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer. Despite its beneficial effects in tumor reduction, the most prevalent side-effect of oxaliplatin treatment is a chemotherapy-induced neuropathy that frequently forces to discontinue the therapy. Indeed, along with direct damage to peripheral nerves, the chemotherapy-related neurotoxicity involves also the central nervous system (CNS) as demonstrated by pain chronicity and cognitive impairment (also known as chemobrain), a newly described pharmacological side effect. The presence of the blood brain barrier (BBB) is instrumental in preventing the entry of the drug into the CNS; here we tested the hypothesis that oxaliplatin might enter the endothelial cells of the BBB vessels and trigger a signaling pathway that induce the disassembly of the tight junctions, the critical components of the BBB integrity. By using a rat brain endothelial cell line (RBE4) we investigated the signaling pathway that ensued the entry of oxaliplatin within the cell. We found that the administration of 10 μM oxaliplatin for 8 and 16 h induced alterations of the tight junction (TJs) proteins zonula occludens-1 (ZO-1) and of F-actin, thus highlighting BBB alteration. Furthermore, we reported that intracellular oxaliplatin rapidly induced increased levels of reactive oxygen species and endoplasmic reticulum stress, assessed by the evaluation of glucose-regulated protein GRP78 expression levels. These events were accompanied by activation of caspase-3 that led to extracellular ATP release. These findings suggested a possible novel mechanism of action for oxaliplatin toxicity that could explain, at least in part, the chemotherapy-related central effects.