Paclitaxel induces neurotoxicity through endoplasmic reticulum stress

作者：Tanimukai Hitoshi^*; Kanayama Daisuke; Omi Tsubasa; Takeda Masatoshi; Kudo Takashi

来源：Biochemical and Biophysical Research Communications, 2013, 437(1): 151-155.

DOI：10.1016/j.bbrc.2013.06.057

• Chemobrain
• Paclitaxel
• Endoplasmic reticulum stress
• BiP
• BIX

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 mu M Px for 24 h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated eIF2 alpha (phospho-eIF2 alpha), 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 mu M 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-eIF2 alpha, 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.

• 出版日期2013-7-19