Osaka University Hospital, Oncology Center, 2-15 Yamadaoka, Suita City, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2013 Jul 19;437(1):151-5. doi: 10.1016/j.bbrc.2013.06.057. Epub 2013 Jun 24.
Due to chemotherapy, the majority of breast cancer patients survive, but frequently complain of chemotherapy-associated cognitive impairment. This phenomenon is termed "chemobrain" or "chemofog" in the literature. However, its mechanisms are unclear. The objective of this study was to investigate the mechanisms of paclitaxel (Px)-induced neurotoxicity, with a focus on endoplasmic reticulum (ER) stress. To investigate Px-induced neurotoxicity and ER stress induction, SK-N-SH cells were treated with 1, 10, 50, and 100 μM Px for 24 h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated elF2α (phospho-eIF2α), C/EBP homologous protein (CHOP), and cleaved caspase 4 and caspase 3 (the active form of each caspase). Furthermore, to investigate whether immunoglobulin heavy-chain binding protein (BiP) inducer X (BIX), which induces the molecular chaperone BiP, could attenuate Px-induced neurotoxicity, SK-N-SH cells were pre-treated for 12 h with 3.5 μM BIX before Px treatment. Neurotoxicity was observed in SK-N-SH cells treated with Px in a dose-dependent manner compared with vehicle control. Furthermore, phospho-eIF2α, CHOP, and activated caspase 4 and caspase 3 were significantly induced in Px-treated cells. In addition, pre-treatment with BIX significantly attenuated the induction of CHOP and activated caspase 4 and caspase 3. The viability of BIX pre-treated cells prior to Px treatment was significantly increased compared with cells that were not treated with BIX. Our results suggest that Px induces neurotoxicity in part through activating the ER stress response. Our findings should contribute to novel approaches regarding the mechanism of Px-induced neurotoxicity, including chemobrain.
由于化疗，大多数乳腺癌患者得以存活，但常抱怨化疗相关认知障碍。这种现象在文献中被称为“化疗脑”或“化疗雾”。然而，其机制尚不清楚。本研究旨在探讨紫杉醇（Px）诱导神经毒性的机制，重点关注内质网（ER）应激。为了研究 Px 诱导的神经毒性和 ER 应激诱导，用 1、10、50 和 100 μM Px 处理 SK-N-SH 细胞 24 小时。用 MTS 活力测定法评估神经毒性，用磷酸化 eIF2α（磷酸化 eIF2α）、C/EBP 同源蛋白（CHOP）和裂解的半胱天冬酶 4 和半胱天冬酶 3（每种半胱天冬酶的活性形式）的表达评估 ER 应激。此外，为了研究免疫球蛋白重链结合蛋白（BiP）诱导物 X（BIX）是否可以减轻 Px 诱导的神经毒性，用 3.5 μM BIX 预处理 SK-N-SH 细胞 12 小时，然后再用 Px 处理。与载体对照相比，Px 以剂量依赖性方式处理 SK-N-SH 细胞，观察到神经毒性。此外，Px 处理的细胞中磷酸化 eIF2α、CHOP 和激活的半胱天冬酶 4 和半胱天冬酶 3 明显诱导。此外，BIX 的预处理显著减轻了 CHOP 和激活的半胱天冬酶 4 和半胱天冬酶 3 的诱导。与未用 BIX 处理的细胞相比，用 Px 处理前用 BIX 预处理的细胞的活力显著增加。我们的结果表明，Px 通过激活 ER 应激反应在一定程度上诱导神经毒性。我们的发现应该有助于研究 Px 诱导神经毒性的机制，包括化疗脑。
