School of Pharmacy, College of Medicine, National Taiwan University, Taipei City, Zhongzheng Dist., Taiwan.
The Metabolomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei City, Zhongzheng Dist., Taiwan.
PLoS One. 2021 Mar 19;16(3):e0248942. doi: 10.1371/journal.pone.0248942. eCollection 2021.
Peripheral neuropathy (PN) is a dose-limiting, painful adverse reaction associated with the use of paclitaxel. This common side effect was often partially attributed to the solvent used for solubilization of the highly hydrophobic drug substance. Therefore, the development of alternative formulations thrived, which included that of Abraxane® containing nanoparticle albumin-bound paclitaxel (nab-paclitaxel). However, studies demonstrated inconsistent conclusions regarding the mitigation of PN in comparison with the traditional formulation. The mass spectrometry-based cell metabolomics approach was used in the present study to explore the potentially associated mechanisms. Although no significant difference in the effects on cell viability was observed, fold changes in carnitine, several acylcarnitines and long-chain fatty acid(s) were significantly different between treatment groups in differentiated and undifferentiated SH-SY5Y cells. The most prominent difference observed was the significant increase of octanoylcarnitine in cells treated with solvent-based paclitaxel, which was found to be associated with significant decrease of medium-chain acyl-CoA dehydrogenase (MCAD). The findings suggested the potential role of altered fatty acid oxidation in the different neurotoxicity patterns observed, which may be a possible target for therapeutic interventions worth further investigation.
周围神经病变（PN）是一种与紫杉醇使用相关的剂量限制、疼痛的不良反应。这种常见的副作用通常部分归因于用于溶解高度疏水性药物物质的溶剂。因此，替代制剂的开发蓬勃发展，包括包含纳米颗粒白蛋白结合紫杉醇（nab-紫杉醇）的 Abraxane®。然而，与传统制剂相比，研究表明关于减轻 PN 的结论不一致。本研究采用基于质谱的细胞代谢组学方法来探索潜在的相关机制。尽管在细胞活力的影响方面没有观察到显著差异，但在分化和未分化的 SH-SY5Y 细胞中，肉碱、几种酰基辅酶 A 和长链脂肪酸（s）的变化倍数在治疗组之间存在显著差异。观察到的最显著差异是在用基于溶剂的紫杉醇处理的细胞中辛酰肉碱的显著增加，这与中链酰基辅酶 A 脱氢酶（MCAD）的显著减少有关。研究结果表明，在观察到的不同神经毒性模式中，脂肪酸氧化的改变可能发挥作用，这可能是值得进一步研究的治疗干预的潜在靶点。
